Piperidine derivatives useful as modulators of chemokine receptor activity

ABSTRACT

The invention provides a compound of formula (I), wherein: T is C(O) or S(O) 2 ; W is C(O) or S(O) 2 ; X is CH 2 , O or NH; Y is CR 5  or N; R 1  is optionally substituted aryl or optionally substituted heterocyclyl; R 2  is hydrogen or C 1-6 alkyl; R 3  is hydrogen or optionally substituted C 1-6 alkyl; and R 4  is alkyl, optionally substituted aryl, optionally substituted aralkyl or optionally substituted heterocyclyl; that are modulators of chemokine (especially CCR3) activity and are especially useful for treating asthma and/or rhinitis.

[0001] The present invention concerns piperidine derivatives havingpharmaceutical activity, to processes for preparing such derivatives, topharmaceutical compositions comprising such derivatives and to the useof such derivatives as active therapeutic agents.

[0002] Pharmaceutically active piperidine derivatives are disclosed inWO99/38514, WO99/04794 and WO00/35877.

[0003] Chemokines are chemotactic cytokines that are released by a widevariety of cells to attract macrophages, T cells, eosinophils, basophilsand neutrophils to sites of inflammation and also play a rôle in thematuration of cells of the immune system. Chemokines play an importantrôle in immune and inflammatory responses in various diseases anddisorders, including asthma and allergic diseases, as well as autoimmunepathologies such as rheumatoid arthritis and atherosclerosis. Thesesmall secreted molecules are a growing superfamily of 8-14 kDa proteinscharacterised by a conserved four cysteine motif. The chemokinesuperfamily can be divided into two main groups exhibitingcharacteristic structural motifs, the Cys-X-Cys (C-X-C, or α) andCys-Cys (C-C, or β) families. These are distinguished on the basis of asingle amino acid insertion between the NH-proximal pair of cysteineresidues and sequence similarity.

[0004] The C-X-C chemokines include several potent chemoattractants andactivators of neutrophils such as interleukin-8 (IL-8) andneutrophil-activating peptide 2 (NAP-2).

[0005] The C-C chemokines include potent chemoattractants of monocytesand lymphocytes but not neutrophils such as human monocyte chemotacticproteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation,Normal T Expressed and Secreted), eotaxin and the macrophageinflammatory proteins 1α and 1β (MIP-1α and MIP-1β.

[0006] Studies have demonstrated that the actions of the chemokines aremediated by subfamilies of G protein-coupled receptors, among which arethe receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5,CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. Thesereceptors represent good targets for drug development since agents whichmodulate these receptors would be useful in the treatment of disordersand diseases such as those mentioned above.

[0007] Histamine is a basic amine, 2-(4-imidazolyl)-ethylamine, and isformed from histidine by histidine decarboxylase. It is found in mosttissues of the body, but is present in high concentrations in the lung,skin and in the gastrointestinal tract. At the cellular levelinflammatory cells such as mast cells and basophils store large amountsof histamine. It is recognised that the degranulation of mast cells andbasophils and the subsequent release of histamine is a fundamentalmechanism responsible for the clinical manifestation of an allergicprocess. Histamine produces its actions by an effect on specifichistamine G-protein coupled receptors, which are of three main types,H1, H2 and H3. Histamine H1 antagonists comprise the largest class ofmedications used in the treatment of patients with allergic disorders,especially rhinitis and urticaria. Antagonists of H1 are useful incontrolling the allergic response by for example blocking the action ofhistamine on post-capillary venule smooth muscle, resulting in decreasedvascular permeability, exudation and oedema. The antagonists alsoproduce blockade of the actions of histamine on the H1 receptors onc-type nociceptive nerve fibres, resulting in decreased itching andsneezing.

[0008] Viral infections are known to cause lung inflammation. It hasbeen shown experimentally that the common cold increases mucosal outputof eotaxin in the airways. Instillation of eotaxin into the nose canmimic some of the signs and symptoms of a common cold. (See, Greiff L etal Allergy (1999) 54(11) 1204-8 [Experimental common cold increasemucosal output of eotaxin in atopic individuals] and Kawaguchi M et alInt. Arch. Allergy Immunol. (2000) 122 S1 44 [Expression of eotaxin bynormal airway epithelial cells after virus A infection].)

[0009] The present invention provides a compound of formula (I):

[0010] wherein:

[0011] T is C(O) or S(O)₂;

[0012] W is C(O) or S(O)₂;

[0013] X is CH₂, O or NH;

[0014] Y is CR⁵ or N;

[0015] R¹ is optionally substituted aryl or optionally substitutedheterocyclyl;

[0016] R² is hydrogen or C₁₋₆ alkyl;

[0017] R³ is hydrogen or optionally substituted C₁₋₆ alkyl;

[0018] R⁴ is alkyl, cycloalkyl, optionally substituted aryl, optionallysubstituted aralkyl or optionally substituted heterocyclyl;

[0019] R⁵ is hydrogen or C₁₋₆ alkyl;

[0020] wherein the foregoing aryl and heterocyclyl moieties areoptionally substituted by: halogen, cyano, nitro, hydroxy, oxo,S(O)_(p)R²⁵, OC(O)NR⁶R⁷, NR⁸R⁹, NR¹⁰C(O)R¹¹, NR¹²C(O)NR¹³R¹⁴,S(O)₂NR¹⁵R¹⁶, NR¹⁷S(O)₂R¹⁸, C(O)NR¹⁹R²⁰, C(O)R²¹, CO₂R²², NR²³CO₂R²⁴,C₁₋₆ alkyl, CF₃, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆ alkoxy, OCF₃, C₁₋₆alkoxy(C₁₋₆)alkoxy (preferably not forming an acetal), C₁₋₆ alkylthio,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl (itself optionallysubstituted by C₁₋₄ alkyl or oxo), methylenedioxy,difluoromethylenedioxy, phenyl, phenyl(C₁₋₄)alkyl, phenoxy, phenylthio,phenyl(C₁₋₄)alkoxy, heteroaryl, heteroaryl(C₁₋₄)alkyl, heteroaryloxy orheteroaryl(C₁₋₄)alkoxy; wherein any of the immediately foregoing phenyland heteroaryl moieties are optionally substituted with halogen,hydroxy, nitro, S(O)_(q)(C₁₋₄ alkyl), S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₄alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃;

[0021] p and q are, independently, 0, 1 or 2;

[0022] R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰,R²¹, R²¹, and R²³ are, independently, hydrogen, C₁₋₆ alkyl (optionallysubstituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₆ alkenyl),phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH₂,NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) orheterocyclyl (itself optionally substituted by halogen, hydroxy, nitro,NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄alkyl, C₁₋₄ alkoxy,C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);

[0023] alternatively NR⁶R⁷, NR⁸R⁹, NR¹³R¹⁴, NR¹⁵R¹⁶, NR¹⁹R²⁰ or N(C₁₋₄alkyl)₂ may, independently, form a 4-7 membered heterocyclic ring,azetidine, pyrrolidine, piperidine, azepine, 1,4-morpholine or1,4-piperazine, the latter optionally substituted by C₁₋₄alkyl on thedistal nitrogen;

[0024] R²⁵, R¹⁸ and R²⁴ are, independently, C₁₋₆ alkyl (optionallysubstituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₆ alkenyl),phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH₂,NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to forma ring as described for R⁶ and R⁷ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups mayjoin to form a ring as described for R⁶ and R⁷ above), cyano, C₁₋₄alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (andthese alkyl groups may join to form a ring as described for R⁶ and R⁷above), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) or heterocyclyl (itself optionallysubstituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂ (and these alkyl groups may join to form a ring as described forR⁶ and R⁷ above), S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl),S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring asdescribed for R⁶ and R⁷ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂,C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may jointo form a ring as described for R⁶ and R⁷ above), CO₂H, CO₂(C₁₋₄ alkyl),NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃);

[0025] or an N-oxide thereof; or a pharmaceutically acceptable saltthereof; or a solvate thereof.

[0026] Certain compounds of the present invention can exist in differentisomeric forms (such as enantiomers, diastereomers, geometric isomers ortautomers). The present invention covers all such isomers and mixturesthereof in all proportions.

[0027] Suitable salts include acid addition salts such as ahydrochloride, dihydrochloride, hydrobromide, phosphate, sulfate,acetate, diacetate, fumarate, maleate, tartrate, citrate, oxalate,methanesulfonate or p-toluenesulfonate. Salts also include metal salts,such as alkali metal salts (for example a sodium salt).

[0028] The compounds of the invention may exist as solvates (such ashydrates) and the present invention covers all such solvates.

[0029] Halogen includes fluorine, chlorine, bromine and iodine.

[0030] Alkyl groups and moieties (including those of alkoxy) arestraight or branched chain and are, for example, methyl, ethyl,n-propyl, 1-methylethyl or 1,1-dimethylethyl.

[0031] Alkenyl is, for example, vinyl or allyl.

[0032] Alkynyl is, for example, propargyl.

[0033] Cycloalkyl is mono-, bi or tricyclic and is, for example,cyclopropyl, cyclopentyl, cyclohexyl, norbornyl or camphoryl. Thecycloalkyl ring is optionally fused to a benzene ring (for exampleforming a bicyclo[4.2.0]octa-1,3,5-trienyl or indanyl ring system).

[0034] Haloalkyl is preferably CF₃. Haloalkoxy is preferably OCF₃.

[0035] Aryl is preferably phenyl or naphthyl.

[0036] Arylalkyl is preferably aryl(C₁₋₄ alkyl) for example benzyl or2-phenyleth-1-yl.

[0037] Heterocyclyl is an aromatic or non-aromatic 5 or 6 membered ring,optionally fused to one or more other rings, comprising at least oneheteroatom selected from the group comprising nitrogen, oxygen andsulfur; or an N-oxide thereof, or an S-oxide or S-dioxide thereof.Heterocyclyl is, for example, furyl, thienyl (also known as thiophenyl),pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl,isoxazolyl, imidazolyl, piperidinyl, morpholinyl, pyridinyl (for examplein 6-oxo-1,6-dihydro-pyridinyl), pyrimidinyl, indolyl,2,3-dihydroindolyl, benzo[b]furyl (also known as benzfuryl),benz[b]thienyl (also known as benzthienyl or benzthiophenyl),2,3-dihydrobenz[b]thienyl (for example in1,1-dioxo-2,3-dihydrobenz[b]thienyl), indazolyl, benzimidazolyl,benztriazolyl, benzoxazolyl, benzthiazolyl (for example in1H-benzthiazol-2-one-yl), 2,3-dihydrobenzthiazolyl (for example in2,3-dihydrobenzthiazol-2-one-yl), 1,2,3-benzothiadiazolyl, animidazopyridinyl (such as imidazo[1,2a]pyridinyl),thieno[3,2-b]pyridin-6-yl 1,2,3-benzoxadiazolyl (also known asbenzo[1,2,3]thiadiazolyl), 2,1,3-benzothiadiazolyl, benzofurazan (alsoknown as 2,1,3-benzoxadiazolyl), quinoxalinyl, dihydro-1-benzopyryliumyl(for example in a coumarinyl or a chromonyl),3,4-dihydro-1H-2,1-benzothiazinyl (for example in2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), a pyrazolopyridine (forexample 1H-pyrazolo[3,4-b]pyridinyl), a purine (for example in3,7-dihydro-purin-2,6-dione-8-yl), quinolinyl, isoquinolinyl (forexample in 2H-isoquinolin-1-one-yl), a naphthyridinyl (for example[1,6]naphthyridinyl or [1,8]naphthyridinyl or in1H-[1,8]naphthyridin-4-one-yl), a benzothiazinyl (for example in4H-benzo[1,4]thiazin-3-one-yl), benzo[d]imidazo[2,1-b]thiazol-2-yl ordibenzothiophenyl (also known as dibenzothienyl); or an N-oxide thereof(such as a pyridine N-oxide), or an S-oxide or S-dioxide thereof.

[0038] An N-oxide of a compound of formula (I) is, for example, a1-oxido-[1,4′]bipiperidinyl-1′-yl compound.

[0039] In one particular aspect the present invention provides acompound of formula (I) wherein: T is C(O) or S(O)₂; W is C(O) or S(O)₂;X is CH₂, O or NH; Y is CR⁵ or N; R¹ is optionally substituted aryl oroptionally substituted heterocyclyl; R² is hydrogen or C₁₋₆ alkyl; R³ ishydrogen or optionally substituted C₁alkyl; R⁴ is alkyl; optionallysubstituted aryl, optionally substituted aralkyl or optionallysubstituted heterocyclyl; R⁵ is hydrogen or C₁₋₆ alkyl; wherein theforegoing aryl and heterocyclyl moieties are optionally substituted by:halogen, cyano, nitro, hydroxy, oxo, S(O)_(p)R²⁵, OC(O)NR⁶R⁷, NR⁸R⁹,NR¹⁰OC(O)R¹¹, NR¹²C(O)NR¹³R¹⁴, S(O)₂NR¹⁵R¹⁶, NR¹⁷S(O)₂R¹⁸, C(O)NR¹⁹R²⁰,C(O)R²¹, CO₂R²², NR²³CO₂R²⁴, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₆alkoxy(C₁)alkyl, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, C₁₋₆ alkoxy(C₁₋₆)alkoxy,C₁₋₆ alkylthio, C₁₋₆ haloalkylthio, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀cycloalkyl (itself optionally substituted by C₁₋₄ alkyl or oxo),methylenedioxy, difluoromethylenedioxy, phenyl, phenyl(C₁₋₄)alkyl,phenoxy, phenylthio, phenyl(C₁₋₄)alkoxy, heteroaryl,heteroaryl(C₁₋₄)alkyl, heteroaryloxy or heteroaryl(C₁₋₄)alkoxy; whereinany of the immediately foregoing phenyl and heteroaryl moieties areoptionally substituted with halogen, hydroxy, nitro, S(O)_(q)(C₁₋₄alkyl), S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),C(O)(C₁₋₄ alkyl), CF₃ or OCF₃; p and q are, independently, 0, 1 or 2;R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷,R¹⁹R²⁰, R²¹, R²², and R²³ are, independently, hydrogen, C₁₋₆ alkyl(optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen,hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), NH(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl),S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl),CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) or heterocyclyl (itself optionallysubstituted by halogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl),C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl),NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃); alternativelyNR⁶R⁷, NR⁸R⁹, NR¹³R¹⁴, NR¹⁵R¹⁶, NR¹⁹R²⁰, may, independently, form a 4-7membered heterocyclic ring, azetidine, pyrrolidine, piperidine, azepine,1,4-morpholine or 1,4-piperazine, the latter optionally substituted byC₁₋₄alkyl on the distal nitrogen; R²⁵, R¹⁸ and R²⁴ are, independently,C₁₋₆ alkyl (optionally substituted by halogen, hydroxy or C₃₋₁₀cycloalkyl), CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted byhalogen, hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and thesealkyl groups may join to form a ring as described for R⁶ and R⁷ above),S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂(and these alkyl groups may join to form a ring as described for R⁶ andR⁷ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl),C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring asdescribed for R⁶ and R⁷ above), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) orheterocyclyl (itself optionally substituted by halogen, hydroxy, nitro,NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkyl groups may join toform a ring as described for R⁶ and R⁷ above), S(O)₂(C₁₋₄ alkyl),S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and these alkylgroups may join to form a ring as described for R⁶ and R⁷ above), cyano,C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂(and these alkyl groups may join to form a ring as described for R⁶ andR⁷ above), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃); or an N-oxide thereof; or apharmaceutically acceptable salt thereof; or a solvate thereof.

[0040] In a further aspect X is O.

[0041] In another aspect R¹ is phenyl substituted with one or more offluorine, chlorine, C₁₋₄ alkyl (especially methyl) or C₁₋₄ alkoxy(especially methoxy).

[0042] In a further aspect R¹ is phenyl optionally substituted (forexample with one, two or three of) by halogen (especially fluoro orchloro), C₁₋₄ alkyl (especially methyl) or C₁₋₄ alkoxy (especiallymethoxy). In a still further aspect R¹ is phenyl substituted by one, twoor three of: fluoro, chloro, methyl or methoxy. In another aspect R¹ isphenyl optionally substituted by halogen (especially fluoro or chloro),C₁₋₄ alkyl (especially methyl); especially optionally substituted (forexample independently with one, two or three of, especially two or threeof) by fluoro, chloro or methyl. In a still further aspect R¹ is3,4-dichlorophenyl, or, additionally 2-chloro-4-fluorophenyl,2-methyl-4-chlorophenyl, 2,4-dichloro-3-methylphenyl or3,4-dichloro-2-methylphenyl.

[0043] In another aspect one of T and W is C(O) and the other is S(O)₂.

[0044] In a still further aspect T is C(O).

[0045] In another aspect W is S(O)₂.

[0046] In yet another aspect of the invention, and when Y is CR⁵, thecompounds of formula (I) are preferably trans in terms of relativestereochemistry, that is, the piperidine ring and the T-N(R³)—W—R⁴ groupare both equatorial on the cyclohexane ring.

[0047] In a still further aspect of the invention Y is CH or N;especially N.

[0048] In yet another aspect R² is hydrogen or methyl; for example R² ishydrogen.

[0049] In a further aspect R³ is hydrogen or methyl; for examplehydrogen.

[0050] In a still further aspect R⁴ is unsubstituted phenyl,mono-substituted phenyl, unsubstituted heterocyclyl or mono-substitutedheterocyclyl, the substituents being chosen from those described above.

[0051] In a further aspect the present inention provides a compound offormula (I) wherein R⁴ is aryl (for example phenyl or naphthyl;especially phenyl) optionally substituted by one or more of C₁₋₆ alkyl(for example methyl or ethyl), C₁₋₄ alkoxy (for example methoxy),halogen (for example chloro or fluoro), CF₃, CN, CO₂(C₁₋₄ alkyl) (forexample CO₂CH₃), OH, OCF₃, S(O)₂(C₁₋₄ alkyl) (for example S(O)₂CH₃) orNR⁸R⁹ (wherein R⁸ and R⁹ are, independently, hydrogen or C₁₋₄ alkyl); orheterocyclyl (for example imidazolyl, thienyl, tetrahydrothienyl,thiazolyl, 1,3,4-thiadiazolyl, pyridyl or dihydroisoquinolinyl)optionally substituted by oxo, halogen (for example chloro or fluoro),C₁₋₄ alkyl (for example methyl), NR⁸R⁹ (wherein R⁸ and R⁹ are,independently, hydrogen or C₁₋₄ alkyl), piperidinyl or morpholinyl. Inanother aspect R⁴ is phenyl optionally substituted by one or more ofC₁₋₆ alkyl (for example methyl or ethyl), C₁₋₄ alkoxy (for examplemethoxy), halogen (for example chloro or fluoro), CF₃, CN, CO₂(C₁₋₄allyl) (for example CO₂CH₃), OH, OCF₃, S(O)₂(C₁₋₄ alkyl) (for exampleS(O)₂CH₃) or NR⁸R⁹ (wherein R⁸ and R⁹ are, independently, hydrogen orC₁₋₄ alkyl).

[0052] In a further aspect of the invention R⁴ is substituted(especially mono-substituted) phenyl, the substituents being chosen fromthose described above.

[0053] In a still further aspect R⁴ is phenyl or heterocyclyl, either ofwhich is optionally substituted by: halo, hydroxy, nitro, cyano, oxo,amino, C₁₋₄ alkyl (itself optionally substituted by S(O)₂(C₁₋₄ alkyl),S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R²⁶ (wherein k is 0, 1 or 2(preferably 2); and R²⁶ is C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₃₋₇cycloalkyl(C₁₋₄ alkyl) (such as cyclopropylmethyl) or phenyl), C₁₋₄haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl) or S(O)₂N(C₁₋₄ alkyl)₂.

[0054] In yet another aspect R⁴ is phenyl or heterocyclyl, either ofwhich is optionally substituted by: halo, hydroxy, nitro, cyano, oxo,NR⁸R⁹ (wherein R⁸ and R⁹ are, independently, hydrogen or C₁₋₄ alkyl),C₁₋₄ alkyl (itself optionally substituted by S(O)₂(C₁₋₄ alkyl),S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R²⁶ (wherein k is 0, 1 or 2(preferably 2); and R²⁶ is C₁₋₄ alkyl, C₁₋₄ hydroxyalkyl, C₃₋₇cycloalkyl(C₁₋₄ alkyl) (such as cyclopropylmethyl) or phenyl), C₁₋₄haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄alkyl) or S(O)₂N(C₁₋₄ alkyl)₂.

[0055] In one aspect the variable R⁴ is phenyl optionally substitutedby: halo, hydroxy, nitro, cyano, amino, C₁₋₄ alkyl (itself optionallysubstituted by S(O)₂(C₁₋₄ alkyl), S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R²⁶(wherein k is 0, 1 or 2 (preferably 2); and R²⁶ is C₁₋₄ alkyl, C₁₋₄hydroxyalkyl, C₃₋₇ cycloalkyl(C₁₋₄ alkyl) (such as cyclopropylmethyl) orphenyl), C₁₋₄ haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl) or S(O)₂N(C₁₋₄ alkyl)₂ (and these alkyl groups mayjoin to form a ring as described for R⁶ and R⁷ above).

[0056] In another aspect the variable R⁴ is phenyl optionallysubstituted by: halo, hydroxy, nitro, cyano, NR⁸R⁹ (wherein R⁸ and R⁹are, independently, hydrogen or C₁₋₆ alkyl), C₁₋₄ alkyl (itselfoptionally substituted by S(O)₂(C₁₋₄ alkyl), S(O)₂phenyl), C₁₋₄ alkoxy,S(O)_(k)R²⁶ (wherein k is 0, 1 or 2 (preferably 2); and R²⁶ is C₁₋₄alkyl, C₁₋₄ hydroxyalkyl, C₃₋₇ cycloalkyl(C₁₋₄ alkyl) (such ascyclopropylmethyl) or phenyl), C₁₋₄ haloalkylthio, C(O)NH₂, NHS(O)₂(C₁₋₄alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl) or S(O)₂N(C₁₋₄ alkyl)₂ (and thesealkyl groups may join to form a ring as described for R⁶ and R⁷ above).

[0057] In another aspect the variable R⁴ is phenyl optionallysubstituted by: halo, hydroxy, nitro, cyano, amino, C₁₋₄ alkyl (itselfoptionally substituted by S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R²⁶(wherein k is 0, 1 or 2; and R²⁶ is C₁₋₄ alkyl or phenyl) or C₁₋₄haloalkylthio.

[0058] In a further aspect the variable R⁴ is phenyl optionallysubstituted by: halo, hydroxy, nitro, cyano, NR⁸R⁹ (wherein R⁸ and R⁹are, independently, hydrogen or C₁₋₄ alkyl), C₁₋₄ alkyl (itselfoptionally substituted by S(O)₂phenyl), C₁₋₄ alkoxy, S(O)_(k)R²⁶(wherein k is 0, 1 or 2; and Re is C₁₋₄ alkyl or phenyl) or C₁₋₄haloalkylthio.

[0059] The amine group NR⁸R⁹ is, for example, mono-(C₁₋₄) alkylamino(such as NHCH₃ or NHCH₂CH₃) or di-(C₁₋₄) alkylamino (such as N(CH₃)₂).

[0060] In yet another aspect of the invention R⁴ is phenylmono-substituted with halogen (for example fluorine or chlorine), C₁₋₄alkyl (for example methyl or ethyl), C₁₋₄ alkoxy (for example methoxy orethoxy) or NR⁸R⁹ (wherein R⁸ and R⁹ are, independently, hydrogen or C₁₋₆alkyl; and NR⁸R⁹ is especially NHCH₃, NHCH₂CH₃ or N(CH₃)₂).

[0061] In a further aspect R⁴ is phenyl substituted with halogen, alkylor alkoxy.

[0062] In a still further aspect of the invention R⁴ is phenylmono-substituted with halogen (especially chlorine) or C₁₋₄ alkyl(especially methyl).

[0063] In yet another aspect R⁵ is hydrogen.

[0064] In another aspect the present invention provides apharmaceutically acceptable salt of a compound of formula (I), forexample a metal salt {such as an alkali metal salt (for example thesodium salt)} of a compound of formula (I).

[0065] Compounds of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and(Ih) are examples of compounds of formula (I).

[0066] In a still further aspect the present invention provides acompound of formula (Ia):

[0067] wherein: X, R¹, R², R³ and R⁴ are as defined above; or apharmaceutically acceptable salt thereof.

[0068] In a still further aspect the present invention provides acompound of formula (Ib):

[0069] wherein: X, R¹, R², R³ and R⁴ are as defined above; or apharmaceutically acceptable salt thereof.

[0070] In a still further aspect the present invention provides acompound of formula (Ic):

[0071] wherein: X, R¹, R², R³, R⁴ and R⁵ are as defined above; or apharmaceutically acceptable salt thereof. In another aspect thecompounds of formula (Ic) are preferably trans in terms of relativestereochemistry, that is, the piperidine ring and the C(O)N(R³)S(O)₂R⁴group are both equatorial on the cyclohexane ring.

[0072] In a still further aspect the present invention provides acompound of formula (Id):

[0073] wherein: X, R¹, R², R³ and R⁴ are as defined above; or apharmaceutically acceptable salt thereof.

[0074] In a still further aspect the present invention provides acompound of formula (Ie):

[0075] wherein: X, R¹, R², R³ and R⁴ are as defined above; or apharmaceutically acceptable salt thereof.

[0076] In a still further aspect the present invention provides acompound of formula (If):

[0077] wherein: X, R¹, R², R³, R⁴ and R⁵ are as defined above; or apharmaceutically acceptable salt thereof. In another aspect thecompounds of formula (If) are preferably trans in terms of relativestereochemistry, that is, the piperidine ring and the S(O)₂N(R³)C(O)R⁴group are both equatorial on the cyclohexane ring.

[0078] In a still further aspect the present invention provides acompound of formula (Ig):

[0079] wherein: X, R¹, R², R³, R⁴ and R⁵ are as defined above; or apharmaceutically acceptable salt thereof. In another aspect thecompounds of formula (Ig) are preferably trans in terms of relativestereochemistry, that is, the piperidine ring and the C(O)N(R³)C(O)R⁴group are both equatorial on the cyclohexane ring.

[0080] In a still further aspect the present invention provides acompound of formula (Ih):

[0081] wherein: X, R¹, R², R³, R⁴ and R⁵ are as defined above; or apharmaceutically acceptable salt thereof. In another aspect thecompounds of formula (Ih) are preferably trans in terms of relativestereochemistry, that is the piperidine ring and the S(O)₂N(R³)S(O)₂R⁴group are both equatorial on the cyclohexane ring.

[0082] A compound of formula (Ia) is, for example:

[0083]N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide;

[0084]N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0085] 4-Chloro-N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0086]2-Chloro-N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0087]N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;

[0088]N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0089]N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0090]4-Chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0091]2-Chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0092]N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;

[0093]N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;

[0094]N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0095]N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0096]N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;

[0097]2-Chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0098]4-Chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0099]N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;

[0100]N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0101] N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0102]N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;

[0103]2-Chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0104]4-Chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0105]N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;

[0106]N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0107]N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;

[0108]N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;

[0109]N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0110]4-Chloro-N-[[(4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0111]2-Chloro-N-[[4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0112]N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-3-trifluoromethyl-benzenesulfonamide;

[0113]3-Cyano-N-[[4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0114]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenemethanesulfonamide;

[0115]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-methanesulfonamide;

[0116]N-[[4-(4-Chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0117]N-[[4-(4-Chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;

[0118]4-Chloro-N-[[4-(4-chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0119] N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-N,4-dimethyl-benzenesulfonamide;

[0120]N-[[4-[(3,4-Dichlorophenyl)methyl][1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;

[0121]4-Chloro-N-[[4-[(3,4-dichlorophenyl)methyl][1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0122]N-[[4-[(3,4-Dichlorophenyl)amino][1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;

[0123]4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0124]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide;

[0125]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0126]3-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0127]4-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0128]3,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0129]3-Cyano-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0130]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethoxy-benzenesulfonamide;

[0131]N-[[4-(3,4-Dichlorophenoxy)([1,4′-bipiperidin]-1′-yl]carbonyl)-3,4-dimethoxy-benzenesulfonamide;

[0132]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(3,3-dimethyl-2-oxo-1-azetidinyl)-benzenesulfonamide;

[0133]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;

[0134]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;

[0135]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-hydroxy-benzenesulfonamide;

[0136]N-[(4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-(trifluoromethyl)-benzenesulfonamide;

[0137]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0138]4-[[[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-benzoicacid, methyl ester;

[0139]2-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0140]N-[5-[[[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-1,3,4-thiadiazol-2-yl]-acetamide;

[0141]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-(dimethylamino)-1-naphthalenesulfonamide;

[0142]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-naphthalenesulfonamide;

[0143]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-dimethyl-5-thiazolesulfonamide;

[0144]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(1-piperidinyl)-3-pyridinesulfonamide;

[0145]5-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;

[0146]5-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;

[0147]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]tetrahydro-3-thiophenesulfonamide;1,1-dioxide

[0148]4,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;

[0149]4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethyl-benzenesulfonamide;

[0150]4-n-Butyl-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0151]2,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-thiophenesulfonamide;

[0152]4-n-Butoxy-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0153]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(trifluoromethoxy)-benzenesulfonamide;

[0154]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-1-methyl-1H-imidazole-4-sulfonamide;

[0155]5-Amino-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-1,3,4-thiadiazole-2-sulfonamide;

[0156]4-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;

[0157]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(4-morpholinyl)-3-pyridinesulfonamide;

[0158]6-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-pyridinesulfonamide;

[0159]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(1,1-dimethylethyl)-benzenesulfonamide;

[0160]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-methyl-2-pyridinesulfonamide;

[0161]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluoro-benzenesulfonamide;

[0162]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(trifluoromethoxy)-benzenesulfonamide;

[0163]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4,5-trifluoro-benzenesulfonamide;

[0164]5-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-difluoro-benzenesulfonamide;

[0165]4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluoro-benzenesulfonamide;

[0166]3-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-fluoro-2-methyl-benzenesulfonamide;

[0167]N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;

[0168]2-chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0169]N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide;

[0170]2-chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0171]N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide;

[0172] N-[[4(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0173]N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]+methyl-benzenesulfonamide;

[0174]N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide,

[0175]2-chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0176]4-chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-15benzenesulfonamide;

[0177] N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;

[0178]N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;

[0179]2-chloro-N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0180]N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0181]2-chloro-N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0182]N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0183]2-chloro-N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0184]4-chloro-N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0185]N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0186]2-chloro-N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;

[0187]4-chloro-N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0188]N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0189]2-chloro-N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0190] 4-chloro-N-([4-(2,5-dichlorophenoxy)[1,4′-bipiperidin]-1′-ylcarbonyl]-benzenesulfonamide;

[0191] 5N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0192]2-chloro-N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0193]N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;

[0194]N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide;

[0195]N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;

[0196]N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0197]3-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0198]N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methoxy-benzenesulfonamide;

[0199]N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4,5-trifluoro-benzenesulfonamide;

[0200]N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl)-2,5-difluoro-benzenesulfonamide;

[0201]N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-(dimethylamino)-benzenesulfonamide;

[0202]N-[[4-(3,4-dichlorophenoxy)(1,4′-bipiperidin]-1′-yl]carbonyl]-2-methoxy-benzenesulfonamide;

[0203]4-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0204]3,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0205] Methyl2-[[[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-benzoate;

[0206] 2-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;

[0207]5-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;

[0208]4,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;

[0209]4-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethyl-benzenesulfonamide;

[0210]2,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-thiophenesulfonamide;

[0211]N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(trifluoromethoxy)-benzenesulfonamide;

[0212]4-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;

[0213]N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin)-1′-yl]carbonyl]-4-(trifluoromethoxy)-benzenesulfonamide;

[0214]5-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-difluoro-benzenesulfonamide;

[0215]4-chloro-N-[[4-(3,4-dichlorophenoxy)([1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluoro-benzenesulfonamide;

[0216]3-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-fluoro-2-methyl-benzenesulfonamide;

[0217]N-[[4-(3,4-dichlorophenoxy)(1,4′-bipiperidin]-1′-yl]carbonyl]-2,6-dimethyl-benzenesulfonamide;or,

[0218]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-propanesulfonamide.

[0219] A compound of formula (Ib) is, for example:

[0220]4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0221]4-(3,4-dichlorophenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0222]N-(4-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0223]4-(3,4-dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0224]4-(3,4-dichlorophenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;

[0225]4-(3,4-dichlorophenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0226]4-(3,4-dichlorophenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0227]4-(3,4-dichlorophenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0228]N-(2-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0229]4-(3,4-dichlorophenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;

[0230]N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0231]4-(4-chloro-2-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0232]N-(4-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0233]4-(4-chloro-2-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0234]4-(4-chloro-2-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;

[0235]4-(4-chloro-2-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0236]4-(4-chloro-2-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0237]4-(4-chloro-2-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0238]N-(2-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0239]4-(4-chloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;

[0240]4-(4-chloro-2-methylphenoxy)-N-(3-cyanobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0241]4-(2,4-dichloro-3-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0242]N-(4-chlorobenzoyl)-4-(2,4-dichloro-3-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0243]4-(2,4-dichloro-3-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0244]4-(2,4-dichloro-3-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-25sulfonamide;

[0245]4-(2,4-dichloro-3-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0246]4-(2,4-dichloro-3-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0247]4-(2,4-dichloro-3-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-30sulfonamide;

[0248]N-(2-chlorobenzoyl)-4-(2,4-dichloro-3-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0249]4-(2,4-dichloro-3-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;

[0250]N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0251]4-(3,4-dichloro-2-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0252]N-(4-chlorobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0253]4-(3,4-dichloro-2-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0254]4-(3,4-dichloro-2-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;

[0255]4-(3,4-dichloro-2-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0256]4-(3,4-dichloro-2-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0257]4-(3,4-dichloro-2-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0258]N-(2-chlorobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0259]4-(3,4-dichloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;

[0260]N-(3-cyanobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0261]N-benzoyl-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0262]N-benzoyl-4-(2,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0263]N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0264]4-(3,4-dichlorophenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0265]4-(3,4-dichlorophenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;

[0266]4-(4-chloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;

[0267]N-(2-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0268]N-(4-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0269]N-(4-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0270]4-(3,4-dichlorophenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0271]4-(3,4-dichlorophenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0272]4-(3,4-dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;

[0273]4-(3,4-dichlorophenoxy)-N-[(1,2-dihydro-1-oxo-4-isoquinolinyl)carbonyl]-[1,4′-bipiperidine]-1′-sulfonamide;

[0274]N-(cyclohexylcarbonyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;

[0275]4-(3,4-dichlorophenoxy)-N-(2-methyl-1-oxopropyl)-[1,4′-bipiperidine)-1′-sulfonamide;

[0276]4-(3,4-dichlorophenoxy)-N-(2-phenylacetyl)-[1,4′-bipiperidine]-1′-sulfonamide;or,

[0277]N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-propanesulfonamide.

[0278] A compound of formula (Ic) is, for example:

[0279] TransN-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-methyl-benzenesulfonamide;

[0280] TransN-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-N,4-dimethyl-benzenesulfonamide;

[0281] Trans4-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;

[0282] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-methyl-benzenesulfonamide;

[0283] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-methyl-benzenesulfonamide;

[0284] Trans3-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;

[0285] Trans4-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;

[0286] Trans3,5-dichloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;

[0287] Trans3-cyano-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;

[0288] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-dimethoxy-benzenesulfonamide;

[0289] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3,4-dimethoxy-benzenesulfonamide;

[0290] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(3,3-dimethyl-2-oxo-1-azetidinyl)-benzenesulfonamide;

[0291] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;

[0292] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;

[0293] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-hydroxy-benzenesulfonamide;

[0294] TransN-[(4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-(trifluoromethyl)-benzenesulfonamide;

[0295] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;

[0296] Trans2-[[[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]amino]-sulfonyl]-benzoicacid, methyl ester;

[0297] Trans2-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;

[0298] TransN-[5-[[[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]amino]sulfonyl]-1,3,4-thiadiazol-2-yl]-acetamide;

[0299] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-5-(dimethylamino)-1-naphthalenesulfonamide;

[0300] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-naphthalenesulfonamide;

[0301] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,4-dimethyl-5-thiazolesulfonamide;

[0302] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-(1-piperidinyl)-3-pyridinesulfonamide;

[0303] Trans5-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-thiophenesulfonamide;

[0304] Trans5-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-thiophenesulfonamide;

[0305] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]tetrahydro-3-thiophenesulfonamide,1,1-dioxide;

[0306] Trans4,5-dichloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl-1-carbonyl)-2-thiophenesulfonamide;

[0307] Trans4-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-dimethyl-benzenesulfonamide;

[0308] Trans4-n-butyl-N-([4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;

[0309] Trans2,5-dichloro-N-[(4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-thiophenesulfonamide;

[0310] Trans4-n-butoxy-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;

[0311] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-(trifluoromethoxy)-benzenesulfonamide;

[0312] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-1-methyl-1H-imidazole-4-sulfonamide;

[0313] Trans5-amino-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-1,3,4-thiadiazole-2-sulfonamide;

[0314] Trans4-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-thiophenesulfonamide;

[0315] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-(4-morpholinyl)-3-pyridinesulfonamide;

[0316] Trans6-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-pyridinesulfonamide;

[0317] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(1,1-dimethylethyl)-benzenesulfonamide;

[0318] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-5-methyl-2-pyridinesulfonamide;

[0319] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-difluoro-benzenesulfonamide;

[0320] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(trifluoromethoxy)-benzenesulfonamide;

[0321] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,4,5-trifluoro-benzenesulfonamide;

[0322] Trans5-chloro-N-[[4[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,4-difluoro-benzenesulfonamide;

[0323] Trans4-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-difluoro-benzenesulfonamide;

[0324] Trans3-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-5-fluoro-2-methyl-benzenesulfonamide;

[0325] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-methyl-benzenesulfonamide;

[0326] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-methoxy-benzenesulfonamide;

[0327] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,6-dimethyl-benzenesulfonamide;

[0328] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-methyl-benzenesulfonamide;

[0329] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;or,

[0330] TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(dimethylamino)-benzenesulfonamide.

[0331] A compound of formula (Id) is, for example:

[0332]4-(3,4-Dichlorophenoxy)-N-(2-methylbenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;

[0333]4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;

[0334]4-(3,4-Dichlorophenoxy)-N-(4-chlorobenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;

[0335]4-(3,4-Dichlorophenoxy)-N-benzoyl-[1,4′-bipiperidine]-1′-carboxamide;

[0336]4-(3,4-Dichlorophenoxy)-N-[(4-methylphenyl)sulfonyl]-[1,4′-bipiperidine]-1′-sulfonamide;or,

[0337]4-(3,4-dichlorophenoxy)-N-[[4-(1,1-dimethylethyl)phenyl)sulfonyl]-[1,4′-bipiperidine]-1′-sulfonamide.

[0338] A compound of formula (Ie) is, for example:

[0339][4-(3,4-dichlorophenoxy)-N-(phenylsulfonyl)-1,4′-bipiperidine]-1′-sulfonamide.

[0340] A compound of formula (If) is, for example:

[0341] TransN-benzoyl-4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanesulfonamide.

[0342] A compound of formula (Ig) is, for example:

[0343] TransN-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzamide.

[0344] A compound of formula (Ih) is, for example:

[0345] TransN-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]sulfonyl]-benzenesulfonamide.

[0346] Compounds of formula (I) (for example compounds of formula (Ia),(Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)) can be prepared by themethods described below.

[0347] A compound of formula (Ic), (If), (Ig) or (Ih) where R³ and R⁵are both hydrogen may be converted to a compound of formula (Ic), (If),(Ig) or (Ih) where R⁵ is alkyl and R³ is hydrogen by deprotonation to adianion, for example with 2 equivalents of LDA, followed by reactionwith an alkylating agent, R⁵Hal (wherein Hal is, for example chlorine).

[0348] A compound of formula (Ic), (If), (Ig) or (Ih) where R⁵ ishydrogen and R³ is not hydrogen may be converted to a compound offormula (Ic), (If), (Ig) or (Ih) where R⁵ is alkyl and R³ is nothydrogen by deprotonation, for example with 1 equivalent of LDA,followed by reaction with an alkylating agent, R⁵Hal.

[0349] A compound of formula (I), wherein R³ is not hydrogen, can beprepared by alkylating a compound of formula (I), wherein R³ ishydrogen, with a suitable alkylating agent (for example R³-L, wherein Lis a leaving group such as triflate, a halide or a diazo group) in thepresence of a suitable base (such as sodium hydride) in a suitablesolvent.

[0350] A compound of formula (I), wherein R³ is hydrogen, T is C(O) andY is N, can be prepared by reacting a compound of formula (II):

[0351] with an isocyanate of formula R⁴N═C═O in the presence of asuitable solvent at a suitable temperature (such as room temperature).Isocyanates of formula R⁴WN═C═O are commercially available or can beprepared by optional adaptation of methods described in the literature.

[0352] A compound of formula (I), wherein T is C(O), W is S(O)₂ and Y isN, can be prepared by reacting a compound of formula (II) with acompound of formula (XXII). A compound of formula (XXII):

[0353] may be prepared from a sulfonamide R⁴SO₂NHR³ and p-nitrophenylchloroformate in the presence of a base, for example triethylamine and acatalyst, for example DMAP, typically at room temperature.

[0354] A compound of formula (II) can be prepared by deprotecting acompound of formula (III):

[0355] for example using trifluoroacetic acid in a suitable solvent(such as dichloromethane) or using a source of hydrogen chloride in asuitable solvent (such as dioxane).

[0356] A compound of formula (III), wherein R² is hydrogen, can beprepared by reacting a compound of formula (IV):

[0357] with a compound of formula (V):

[0358] in the presence of NaBH(OAc)₃ and acetic acid.

[0359] A compound of formula (E), wherein R² is C₁₋₆ alkyl, can beprepared by reacting a compound of formula (XVII):

[0360] with a Grignard reagent of formula R²MgHal (wherein Hal ischlorine, bromine or iodine) in a suitable solvent, such astetrahydrofuran.

[0361] A compound of formula (XVII) can be prepared by reacting acompound of formula (IV) with a compound of formula (V) in the presenceof titanium tetrisopropoxide, for example in dichloroethane, followed bythe addition of diethylaluminium cyanide to a solution, for example intoluene.

[0362] A compound of formula (I), wherein R³ is hydrogen, T is S(O)₂, Wis C(O) and Y is N, can be prepared by reacting a compound of formula(IX):

[0363] with a compound of formula (II) in the presence of a suitablebase (such as triethylamine) in a suitable solvent (such astetrahydrofuran) at a suitable temperature (such as below −60° C.). Acompound of formula (IX) can be prepared by reacting an acid R⁴CO₂H withClS(O)₂N═C═O, for example below 80° C.

[0364] Alternatively, a compound of formula (I), wherein R³ is hydrogen,T is S(O)₂, W is C(O) and Y is N, can be prepared by reacting a compoundof formula (XVIII):

[0365] with an acyl halide R⁴COHal in the presence of a base, forexample triethylamine in a suitable solvent, for exampledichloromethane, for example at room temperature.

[0366] A compound of formula (XVIII) may be prepared by the reaction ofa compound of formula (II) with sulfamide, for example in dioxan atreflux.

[0367] A further method of preparing a compound of formula (I), whereinR³ is hydrogen, T is S(O)₂, W is C(O) and Y is N, is to react a compoundof formula (XIX):

[0368] with an acyl halide R⁴COHal in the presence of a base, forexample triethylamine in a suitable solvent, for exampledichloromethane, for example at room temperature, followed bydeprotection of the carbamate so formed, for example withtrifluoroacetic acid in dichloromethane.

[0369] A compound of formula (XIX) can be prepared from a compound offormula (II) and a compound of formula (XX):

[0370] in a suitable solvent for example dichloromethane typically atroom temperature.

[0371] A compound of formula (I) wherein T and W are both S(O)₂ and Y isN, can be prepared by reacting a compound of formula (X):

[0372] with a sulfonamide R⁴S(O)₂NHR³ in the presence of a base (such ascalcium oxide), in a suitable solvent (such as DMSO) at a temperaturepreferably in the range 50-110° C. (For example see DE 1618439; DE1249259; Chemical Abstracts 1967, 67, 116716a). A compound of formula(X) can be prepared by reacting a compound of formula (II) with S(O)₂Cl₂in the presence of a suitable base (such as triethylamine).

[0373] Alternatively, a compound of formula (I) wherein T and W are bothS(O)₂ and Y is N, can be prepared by reacting a compound of formula(XVIII) with a sulfonyl chloride R⁴SO₂Cl in the presence of a base, forexample triethylamine, preferably with dimethylaminopyridine as catalystin a suitable solvent, for example dichloromethane, for example at roomtemperature.

[0374] A compound of formula (I) wherein T is C(O), W is S(O)₂ and Y isCR⁵, can be prepared by firstly hydrolysing a compound of formula (XI):

[0375] wherein the ester is preferably a C₁₋₆ alkyl group, and reactingthe product so formed with R⁴S(O)₂NHR³ in the presence of an appropriatecoupling agent (such as ethyl dimethylaminopropyl carbodiimide (EDCI),with 4-dimethylaminopyridine (DMAP) or 1-hydroxybenzotriazole (HOBT)) ina suitable solvent, for example DMF.

[0376] A compound of formula (XI), wherein R² is hydrogen, can beprepared by reductively aminating a compound of formula (XI):

[0377] with a compound of formula (XIII):

[0378] A compound of formula (X) where R² is alkyl can be prepared byamino nitrile formation between compounds of formula (XII) and (XIII)followed by displacement of the nitrile with a grignard reagent.

[0379] A compound of formula (I), wherein T and W are both C(O) and Y isCH or N, can be prepared by heating a compound of formula (XIV):

[0380] in the presence of R⁴C(OR′)₂N(CH₃)₂ or R⁴C(OR′)₃, wherein R′ ismethyl or ethyl, or (OR′)₃ is (OCH₂)₃CCH₃. A compound of formula (XI)where Y is CR⁵ can be prepared by firstly hydrolysing a compound offormula (XI) and then coupling the product so formed with an amine R³NH₂in the presence of an appropriate coupling agent (such as ethyldimethylaminopropyl carbodiimide, with 4-dimethylaminopyridine or1-hydroxybenzotriazole) in a suitable solvent, for example DMF. Acompound of formula (XIV) where Y is N and R³ is H may be prepared byreaction of a compound of formula (II) with sodium cyanate in thepresence of an acid, for example acetic acid. A compound of formula(XIV) where Y is N and R³ is alkyl may be prepared by reaction of acompound of formula (II) with a compound of formula (XXI): R³—N═C═O; inan inert solvent, for example dichloromethane, for example at roomtemperature.

[0381] A compound of formula (I), wherein T is S(O)₂, W is C(O) and Y isCR⁵, can be prepared by coupling a compound of formula (XV):

[0382] to an acid R⁴CO₂H in the presence of an appropriate couplingagent (such as ethyl dimethylaminopropyl carbodiimide,4-dimethylaminopyridine or HOBT) in a suitable solvent.

[0383] A compound of formula (I), wherein T and W are both S(O)₂ and Yis CH, can be prepared by coupling a compound of formula (XV) to asulfonyl chloride R⁴S(O)₂CH, in the presence of a base and a solvent(such as dichloromethane, N,N-dimethylformamide or tetrahydrofuran).

[0384] A compound of formula (XV) can be prepared by reductivelyaminating a compound of formula (XVI):

[0385] with a compound of formula (IV) to obtain a compound wherein R²is hydrogen, or aminonitrile formation followed by a Grignard reactionto obtain a compound wherein R² is alkyl.

[0386] A compound of formula (XVI) can be prepared by reacting

[0387] with CH₂═CR⁵—S(O)₂NHR³ at an elevated temperature (such as inrefluxing toluene) and then hydrolysing the silyl enol ether (such aswith acetic acid).

[0388] A compound of formula (I) where Y is CR⁵ and R⁵ is not hydrogenmay be prepared from a compound of formula (I) where Y is CH by reactionof the dianion (R³ is H) or monoanion (R³ is alkyl) (formed with asuitable base, for example LDA) with an alkylating agent (for exampleR⁵-L, wherein L is a leaving group such as triflate or a halide) in asuitable solvent for example THF for example at 0° or below.

[0389] Further compounds of formula (I) can be prepared by adaptationof: the routes described above, methods described in the art or theExamples recited below. The intermediates identified above arecommercially available or can be prepared by using or adapting methodsdescribed in the art.

[0390] In another aspect the present invention provides processes forthe preparation of compounds of formula (I) (for example a compound offormula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)).

[0391] The intermediates of formula (X), (XI), (XIV), (XV), (XVI) and(XIX) defined herein are novel and these, and processes for theirpreparation, are provided as further features of the invention.

[0392] The compounds of the invention have activity as pharmaceuticals,in particular as modulators of chemokine receptor (especially CCR3)activity, and may be used in the treatment of autoimmune, inflammatory,proliferative or hyperproliferative diseases, orimmunologically-mediated diseases (including rejection of transplantedorgans or tissues and Acquired Immunodeficiency Syndrome (AIDS)).

[0393] In one aspect examples of these conditions are:

[0394] (1) (the respiratory tract) obstructive diseases of airwaysincluding: chronic obstructive pulmonary disease (COPD) (such asirreversible COPD); asthma {such as bronchial, allergic, intrinsic,extrinsic or dust asthma, particularly chronic or inveterate asthma (forexample late asthma or airways hyper-responsiveness)}; bronchitis {suchas eosinophilic bronchitis}; acute, allergic, atrophic rhinitis orchronic rhinitis including rhinitis caseosa, hypertrophic rhinitis,rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranousrhinitis including croupous, fibrinous or pseudomembranous rhinitis orscrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hayfever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related,diseases; nasal polyposis; fibroid lung, idiopathic interstitialpneumonia, antittissive activity, treatment of chronic cough associatedwith inflammatory conditions of the airways or iatrogenic induced cough;

[0395] (2) (bone and joints) arthrides including rheumatic, infectious,autoimmune, seronegative spondyloarthropathies (such as ankylosingspondylitis, psoriatic arthritis or Reiter's disease), Behçet's disease,Sjogren's syndrome or systemic sclerosis;

[0396] (3) (skin and eyes) psoriasis, atopic dermatitis, contactdermatitis or other eczmatous dermitides, seborrhoetic dermatitis,Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias,uveitis, Alopecia greata or vernal conjunctivitis;

[0397] (4) (gastrointestinal tract) Coeliac disease, proctitis,eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerativecolitis, irritable bowel disease or food-related allergies which haveeffects remote from the gut (for example migraine, rhinitis or eczema);

[0398] (5) (Allograft rejection) acute and chronic following, forexample, transplantation of kidney, heart, liver, lung, bone marrow,skin or cornea; or chronic graft versus host disease; and/or

[0399] (6) (other tissues or diseases) Alzheimer's disease, multiplesclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS),Lupus disorders (such as lupus erythematosus or systemic lupus),erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type Idiabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,leprosy (such as leprornatous leprosy), Peridontal disease, Sezarysyndrome, idiopathic thrombocytopenia pupura or disorders of themenstrual cycle.

[0400] The compounds of the invention are also H1 antagonists and may beused in the treatment of allergic disorders.

[0401] The compounds of the invention may also be used to control a signand/or symptom of what is commonly referred to as a cold (for example asign and/or symptom of a common cold or influenza or other associatedrespiratory virus infection).

[0402] According to a further feature of the invention there is provideda compound of formula (I) (for example a compound of formula (Ia), (Ib),(Ic), (Id), (Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptablesalt thereof or a solvate thereof, for use in a method of treatment of awarm blooded animal (such as man) by therapy (including prophylaxis).

[0403] According to a further feature of the present invention there isprovided a method for modulating chemokine receptor activity (especiallyCCR3 receptor activity), or antagonising H1, in a warm blooded animal,such as man, in need of such treatment, which comprises administering tosaid animal an effective amount of a compound of the formula (I) (forexample a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig)or (Ih)), or a pharmaceutically acceptable salt thereof or a solvatethereof.

[0404] The invention also provides a compound of the formula (I) (forexample a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig)or (Ih)), or a pharmaceutically acceptable salt thereof or a solvatethereof, for use as a medicament.

[0405] In another aspect the invention provides the use of a compound offormula (I) (for example a compound of formula (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereofor a solvate thereof, in the manufacture of a medicament for use intherapy (for example modulating chemokine receptor activity (especiallyCCR3 receptor activity), or antagonising H1, in a warm blooded animal,such as man).

[0406] The invention further provides the use of a compound of formula(I) (for example a compound of formula (Ia), (Ib), (Ic), (Id), (Ie),(If), (Ig) or (Ih)), or a pharmaceutically acceptable salt thereof, inthe manufacture of a medicament for use in the treatment of:

[0407] (1) (the respiratory tract) obstructive diseases of airwaysincluding: chronic obstructive pulmonary disease (COPD) (such asirreversible COPD); asthma {such as bronchial, allergic, intrinsic,extrinsic or dust asthma, particularly chronic or inveterate asthma (forexample late asthma or airways hyper-responsiveness)}; bronchitis {suchas eosinophilic bronchitis}; acute, allergic, atrophic rhinitis orchronic rhinitis including rhinitis caseosa, hypertrophic rhinitis,rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranousrhinitis including croupous, fibrinous or pseudomembranous rhinitis orscrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hayfever) or vasomotor rhinitis; sarcoidosis; farmer's lung and relateddiseases; nasal polyposis; fibroid lung, idiopathic interstitialpneumonia, antitussive activity, treatment of chronic cough associatedwith inflammatory conditions of the airways or iatrogenic induced cough;

[0408] (2) (bone and joints) arthrides including rheumatic, infectious,autoimmune, seronegative spondyloarthropathies (such as ankylosingspondylitis, psoriatic arthritis or Reiter's disease), Behçet's disease,Sjogren's syndrome or systemic sclerosis;

[0409] (3) (skin and eyes) psoriasis, atopic dermatitis, contactdermatitis or other eczmatous dermitides, seborrhoetic dermatitis,Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa,urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias,uveitis, Alopecia greata or vernal conjunctivitis;

[0410] (4) (gastrointestinal tract) Coeliac disease, proctitis,eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerativecolitis, irritable bowel disease or food-related allergies which haveeffects remote from the gut (for example migraine, rhinitis or eczema);

[0411] (5) (Allograft rejection) acute and chronic following, forexample, transplantation of kidney, heart, liver, lung, bone marrow,skin or cornea; or chronic graft versus host disease; and/or

[0412] (6) (other tissues or diseases) Alzheimer's disease, multiplesclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS),Lupus disorders (such as lupus erythematosus or systemic lupus),erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type Idiabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome,leprosy (such as lepromatous leprosy), Peridontal disease, sezarysyndrome, idiopathic thrombocytopenia pupura or disorders of themenstrual cycle;

[0413] in a warm blooded animal, such as man.

[0414] In a further aspect a compound of formula (I) (for example acompound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)),or a pharmaceutically acceptable salt thereof, is useful in thetreatment of asthma {such as bronchial, allergic, intrinsic, extrinsicor dust asthma, particularly chronic or inveterate asthma (for examplelate asthma or airways hyper-responsiveness)}; or rhinitis {includingacute, allergic, atrophic or chronic rhinitis, such as rhinitis caseosa,hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitismedicamentosa; membranous rhinitis including croupous, fibrinous orpseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitisincluding rhinitis nervosa (hay fever) or vasomotor rhinitis}.

[0415] In a still further aspect a compound of formula (I) (for examplea compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)),or a pharmaceutically acceptable salt thereof, is useful in thetreatment of asthma.

[0416] The present invention also provides the use of a compound offormula (I) (for example a compound of formula (Ia), (Ib), (Ic), (Id),(Ie), (If), (Ig) or (Ih)), or a pharmaceutically acceptable saltthereof, in the manufacture of a medicament for use in the treatment ofasthma or rhinitis.

[0417] The present invention further provides a method of treating achemokine mediated disease state (especially a CCR3 mediated diseasestate, especially asthma) in a warm blooded animal, such as man, whichcomprises administering to a mammal in need of such treatment aneffective amount of a compound of formula (I) (for example a compound offormula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or apharmaceutically acceptable salt thereof or solvate thereof.

[0418] In order to use a compound of the invention, or apharmaceutically acceptable salt thereof or solvate thereof, for thetherapeutic treatment of a warm blooded animal, such as man, inparticular modulating chemokine receptor (for example CCR3 receptor)activity or antagonising H1, said ingredient is normally formulated inaccordance with standard pharmaceutical practice as a pharmaceuticalcomposition.

[0419] Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)(for example a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If),(Ig) or (Ih)), or a pharmaceutically acceptable salt thereof or asolvate thereof (active ingredient), and a pharmaceutically acceptableadjuvant, diluent or carrier. In a further aspect the present inventionprovides a process for the preparation of said composition whichcomprises mixing active ingredient with a pharmaceutically acceptableadjuvant, diluent or carrier. Depending on the mode of administration,the pharmaceutical composition will preferably comprise from 0.05 to 99%w (percent by weight), more preferably from 0.05 to 80% w, still morepreferably from 0.10 to 70% w, and even more preferably from 0.10 to 50%w, of active ingredient, all percentages by weight being based on totalcomposition.

[0420] The pharmaceutical compositions of this invention may beadministered in standard manner for the disease condition that it isdesired to treat, for example by topical (such as to the lung and/orairways or to the skin), oral, rectal or parenteral administration. Forthese purposes the compounds of this invention may be formulated bymeans known in the art into the form of, for example, aerosols, drypowder formulations, tablets, capsules, syrups, powders, granules,aqueous or oily solutions or suspensions, (lipid) emulsions, dispersiblepowders, suppositories, ointments, creams, drops and sterile injectableaqueous or oily solutions or suspensions.

[0421] A suitable pharmaceutical composition of this invention is onesuitable for oral administration in unit dosage form, for example atablet or capsule which contains between 0.1 mg and 1 g of activeingredient.

[0422] In another aspect a pharmaceutical composition of the inventionis one suitable for intravenous, subcutaneous or intramuscularinjection.

[0423] Each patient may receive, for example, an intravenous,subcutaneous or intramuscular dose of 0.01 mgkg⁻¹ to 100 mgkg⁻¹ of thecompound, preferably in the range of 0.1 mgkg⁻¹ to 20 mgkg⁻¹ of thisinvention, the composition being administered 1 to 4 times per day. Theintravenous, subcutaneous and intramuscular dose may be given by meansof a bolus injection. Alternatively the intravenous dose may be given bycontinuous infusion over a period of time. Alternatively each patientwill receive a daily oral dose which is approximately equivalent to thedaily parenteral dose, the composition being administered 1 to 4 timesper day.

[0424] The following illustrate representative pharmaceutical dosageforms containing the compound of formula (I) (for example a compound offormula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) or (Ih)), or apharmaceutically-acceptable salt thereof (hereafter Compound X), fortherapeutic or prophylactic use in humans: mg/tablet (a) Tablet ICompound X 100 Lactose Ph. Eur. 179 Croscarmellose sodium 12.0Polyvinylpyrrolidone 6 Magnesium stearate 3.0 (b) Tablet II Compound X50 Lactose Ph. Eur. 229 Croscarmellose sodium 12.0 Polyvinylpyrrolidone6 Magnesium stearate 3.0 (c) Tablet III Compound X 1.0 Lactose Ph. Eur.92 Croscarmellose sodium 4.0 Polyvinylpyrrolidone 2.0 Magnesium stearate1.0 mg/capsule (d) Capsule Compound X 10 Lactose Ph. Eur. 389Croscarmellose sodium 100 Magnesium stearate 1.0 (50 mg/ml) (e)Injection I Compound X 5.0% w/v Isotonic aqueous solution to 100%

[0425] Buffers, pharmaceutically-acceptable cosolvents such aspolyethylene glycol, polypropylene glycol, glycerol or ethanol orcomplexing agents such as hydroxy-propyl β-cyclodextrin may be used toaid formulation.

[0426] The above formulations may be obtained by conventional procedureswell known in the pharmaceutical art. The tablets (a)-(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

[0427] The invention will now be illustrated by the followingnon-limiting Examples in which, unless stated otherwise:

[0428] (i) when given, ¹H NMR data is quoted and is in the form of deltavalues for major diagnostic protons, given in parts per million (ppm)relative to tetramethylsilane (TMS) as an internal standard, determinedat 300 MHz or 400 MHz using perdeuterio DMSO-D6 (CD₃SOCD₃), methanol-D4(CD₃OD) or CDCl₃ as the solvent unless otherwise stated;

[0429] (ii) mass spectra (MS) were run with an electron energy of 70electron volts in the chemical ionisation (CI) mode using a directexposure probe; where indicated ionisation was effected by electronimpact (EI) or fast atom bombardment (FAB) or electrospray (ESI); wherevalues for m/z are given, generally only ions which indicate the parentmass are reported, and unless otherwise stated the mass ion quoted isthe positive mass ion—(M+H)⁺;

[0430] (iii) the title and sub-title compounds of the examples andmethods were named using the ACD/Index name program version 4.55 fromAdvanced Chemistry Development, Inc;

[0431] (iv) unless stated otherwise, reverse phase HPLC was conductedusing a Symmetry, NovaPak or Xterra reverse phase silica column; and

[0432] (v) the following abbreviations are used: RPHPLC reverse phaseHPLC DEAD diethyl-azodicarboxylate NMP N-methylpyrrolidone CDIN,N′-carbonyl diimidazole MTBE tert-butyl methyl ether DMFN,N-dimethylformamide HOBT 1-hydroxybenzotriazole Boc or BOCtert-butoxycarbonyl HPLC high pressure liquid chromatography EDCI Ethyldimethylaminopropyl carbodiimide TMEDA TertamethylethylenediaminePYBROP ™ bromo-tris-pyrrolidino-phosphonium hexafluorophosphate THFtetrahydrofuran DCM dichloromethane TFA trifluoroacetic acid m. pt.melting point DMSO dimethylsulfoxide Ac Acetate aq aqueous RT roomtemperature IPA iso-propyl alcohol LDA Lithium diisopropylamide equiv.equivalents

EXAMPLE 1A

[0433]N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide(an Example of a Compound of Formula (Ia)).

[0434] To a solution of 4-(3,4-dichlorophenoxy)-1,4′-bipiperidine(Method C; 0.197 g) in dichloromethane (5 ml) was added4-fluorobenzenesulfonyl isocyanate (0.121 g) dropwise and the reactionwas stirred under nitrogen for 12 hours. The solvent was removed underreduced pressure and the resulting product was purified by RPHPLC(Waters Xterra® column), (gradient, 75:25 0.2% aq ammonia/acetonitrileto 5:95 over 10 mins) to give the title compound (60 mg; MS (M+H]⁺(APCI+) 530/532).

[0435]¹H NMR (399.98 MHz, CD₃OD) δ 1.50-1.61 (m, 2H), 2.01-2.24 (m, 6H),2.64-2.73 (m, 2H), 3.25-3.43 (m, 5H), 4.42-4.50 (m, 2H), 4.64-4.71 (m,1H), 6.95-6.98 (m, 1H), 7.12-7.16 (m, 2H), 7.21-7.22 (m, 1H), 7.41-7.44(m, 1H), 7.90-7.95 (m, 2H).

[0436] The Examples 1B-1AV are examples of compounds of formula (Ia) andwere prepared using similar methodology to that of Example 1A.Recrystallisation was required after chromatography for severalExamples.

EXAMPLE 2A

[0437]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenemethanesulfonamide(an Example of a Compound of Formula (Ia)).

[0438] To a stirred solution of para-nitrophenylchloroformate (0.141 g)in dichloromethane (5 ml) was added dimethylaminopyridine (0.086 g).After 2 minutes benzenemethanesulfonamide (0.120 g) was added followedby triethylamine (0.078 g). After 30 minutes4-(3,4-dichlorophenoxy)-1,4′-bipiperidine (Method C; 0.230 g) was addedand the reaction was left to stir for 2 hours. The solvent was removedunder reduced pressure and the resulting product was purified by RPHPLC(Waters Xterra® column), (gradient, 90:10 0.2% aq ammonia/acetonitrileto 5:95 over 6 mins) to give the title compound (202 mg).

[0439]¹H NMR (399.98 MHz, CD₃OD) δ 1.30-1.43 (m, 2H), 1.73-1.84 (m, 4H),1.98-2.06 (m, 2H), 2.44-2.55 (m, 3H), 2.59-2.66 (m, 2H), 2.82-2.89 (m,2H), 4.36-4.42 (m, 3H), 4.41 (s, 2H), 6.88-6.91 (m, 1H), 7.09-7.10 (m,1H), 7.24-7.31 (m, 3H), 7.36-7.39 (m, 3H); plus 1 drop of 30% NaOD inD₂O.

[0440] ES+ 526/528

[0441] The Examples 2B-2X are examples of compounds of formula (Ia) andwere prepared using similar methodology to that of Example 2A.

EXAMPLE 3A

[0442]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-N,4-dimethyl-benzenesulfonamide(an Example of a Compound of Formula (Ia) where R³ is not Hydrogen).

[0443] To a solution ofN-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide(Example 1B, 0.3 g) in methanol/dichloromethane (1:1, 40 ml) was added(trimethylsilyl)diazomethane (2M in hexanes) (5 ml) dropwise. Thereaction was stirred under nitrogen for 12 hours. The solvent wasremoved under reduced pressure and the resulting product was purified byRPHPLC (Waters Xterra® column), (gradient, 75:25 0.2% aq ammoniaacetonitrile to 5:95 over 6 mins) to give the title compound (83 mg).

[0444]¹H NMR (399.98 MHz, CD₃OD) δ 1.42-1.53 (m, 2H), 1.63-1.71 (m, 2H),1.82-1.96 (m, 4H), 2.31 (s, 3H), 2.39-2.47 (m, 2H), 2.48-2.57 (m, 1H);2.72-2.79 (m, 2H), 2.93-3.01 (m, 2H), 3.69 (s, 3H), 4.20-4.26 (m, 2H),4.27-4.34 (m, 1H), 6.77-6.81 (m, 1H), 7.00 (d, 1H), 7.21-7.29 (m, 3H),7.65-7.68 (m, 2H)

[0445] ES+ 540/542; m. pt. 151-153° C.

EXAMPLE 4A

[0446]N-Benzoyl-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide (anExample of a Compound of Formula (Ib)).

[0447] Benzoyl sulfamoyl chloride (DE931225, (1955) Chemical Abstracts1956, 50, 7861a; 248 mg) was dissolved in THF (5 ml) and cooled to −78°C. Triethylamine (170 μl) was added dropwise over 160s and the solutionwas stirred for 25 min. 4-(3,4-Dichlorophenoxy)-1,4′-bipiperidine(Method C; 329 mg) in THF (5 ml) was added dropwise over 35 min. Waterwas added then the mixture was evaporated. The residue was purified byRPHPLC (Waters Xterra® Column, eluant 0.1% aq ammoniumacetate:acetonitrile 75-5:25-95) to give the title compound (37 mg; MS[M+H]⁺ (APCI+) 512/514).

[0448]¹H NMR (399.98 MHz, DMSO) δ 1.59 (qd, 2H), 1.74-1.84 (m, 2H), 1.96(d, 2H), 2.06 (d, 2H), 2.76 (t, 2H), 2.86-3.03 (m, 3H), 3.08-3.17 (m,2H), 3.71 (d, 2H), 4.57-4.64 (m, 1H), 7.02 (dd, 1H), 7.32 (d, 1H), 7.37(t, 2H), 7.45 (t, 1H), 7.53 (d, 1H), 7.92 (d, 2H).

EXAMPLE 5A

[0449]N-Benzoyl-4-(2,4-dichloro-3-methylphenoxy)-[1,4′-bipiperidine)-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

[0450] 4-(2,4-Dichloro-3-methylphenoxy)-1,4′-bipiperidine (see Method C;240 mg) was dissolved in dichloromethane (10 ml). Triethylamine (107 μl)was added followed by benzoyl sulfamoyl chloride (154 mg). The solutionwas stirrred for 12 h and then concentrated. The residue was purified byby RPHPLC (Waters Xterra® column), (gradient, 90:10 0.2% aqammonia/acetonitrile to 5:95 over 6 mins) to give the title compound.(70 mg, MS [M+H]⁺ (APCI+) 526/528; m.pt. 223° C.)

[0451]¹H NMR (399.98 MHz, CD₃OD) δ 8.00-8.03 (m, 2H), 7.38-7.43 (m, 1H),7.31-7.36 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 4.45-4.52 (m, 1H),3.80-3.87 (m, 2H), 2.84-2.92 (m, 2H), 2.73-2.81 (m, 2H), 2.51-2.58 (m,2H), 2.44 (s, 3H), 2.38-2.44 (m, 1H), 1.91-2.03 (m, 4H), 1.80-1.89 (m,2H), 1.59-1.70 (m, 2H); plus 1 drop of 30% NaOD in D₂O.

[0452] The Examples 5B-5E are examples of compounds of formula (Ia) andwere prepared using similar methodology to that of Example 5A.

EXAMPLE 6A

[0453] trans4-Chloro-N-[[(4-[(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]-carbonyl]-benzenesulfonamide(an Example of a Compound of Formula (Ic)).

[0454] Sodium4-[4-(3,4-dichlorophenoxy)-1-piperidinyl)-cyclohexanecarboxylate (MethodF, 111 mg), EDCI (99 mg), HOBT (97 mg), DMAP (32 mg) andp-chlorobenzenesulfonamide (98 mg) were combined in DMF (3 ml) andstirred overnight. The solvent was evaporated and the residue waspurified by RPHPLC (Waters Xterra® Column, eluant 0.1% aqueous ammoniumacetate:acetonitrile 75-25:25-75) to give the title compound (18 mg; MS[M+H]⁺ (APCI+) 545/547/549).

[0455]¹H NMR (399.98 MHz, DMSO) δ 1.23 (q, 2H), 1.35 (q, 2H), 1.74-1.97(m, 7H), 2.02-2.11 (m, 21), 2.88-3.07 (m, 4H), 3.09-3.21 (m, 2H),4.56-4.67 (m, 1H), 7.02 (dd, 1H), 7.33 (d, 1H), 7.46 (d, 2H), 7.53 (d,1H), 7.73 (d, 2H).

EXAMPLE 7A

[0456]N-Benzoyl-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxamide (anExample of a Compound of Formula (Id)).

[0457] 4-(3,4-Dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxamide(Method H, 200 mg) and triethylorthobenzoate (3 ml) were heated at 150°C. for 16 h, then allowed to reach ambient temperature. 2M HCl (2 ml)was added and the resulting solution was stirred for 4 h. The volatileswere evaporated and the residue was purified by chromatography (24:1dichloromethane: methanol) followed by RPHPLC (Waters Xterra® column),(gradient, 75:25 0.2% aq ammonia/acetonitrile to 5:95 over 6 mins) togive the title compound (m.pt. 65-80° C.; MS [M+H]⁺ (ES+) 476/478).

[0458]¹H NMR (399.98 MHz, DMSO) δ 1.42 (2H, d), 1.58 (2H, d), 1.76 (2H,d), 1.92 (2H, d), 2.39 (2H, t), 2.72-2.78 (2H, m), 2.81-2.94 (3H, m),3.79-4.22 (2H, m), 4.42 (1H, t), 6.98 (1H, dd), 7.25 (1H, d), 7.44-7.52(3H, m), 7.56-7.68 (1H, m), 7.83-7.92 (2H, m).

EXAMPLE 8A

[0459]N-(3,4-Dichlorobenzoyl)-4-(3,4-dichlorophenoxy)-(1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

[0460] 4-(3,4-Dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide(Method G, 200 mg), 3,4 dichlorobenzoylchloride (102 mg) andtriethylamine (0.07 ml) were stirred together in dichloromethane (10 ml)at ambient temperature for 24 hours. The solvent was evaporated and theresulting product was purified by RPHPLC (Waters Xterra® column),(gradient, 5:25 0.2% aq ammonia/acetonitrile to 5:95 over 6 mins) togive the title compound (22 mg; m.pt. 166-167° C.; MS APCI 580/582/584(M+H)).

[0461]¹H NMR (399.98 MHz, DMSO) δ 1.57-1.79 (m, 4H), 1.89-2.17 (m, 5H),2.60-2.76 (m, 2H), 3.06-3.25 (m, 2H), 3.36-3.60 (m, 2H), 3.60-3.76 (m,2H), 4.54-4.87 (m, 1H), 6.93-7.11 (m, 1H), 6.93-7.11 (m, 1H), 7.30-7.40(m, 1H), 7.49-7.66 (m, 2H), 7.85 (d, 1H), 8.12 (s, 1H).

[0462] The Examples 8B-8F are examples of compounds of formula (Ib) andwere prepared using similar methodology to that of Example 8A.Recrystallisation was required after chromatography for severalExamples.

EXAMPLE 9A

[0463]4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

[0464]1,1-Dimethylethyl[4-(3,4-dichlorophenoxy)-1,4′-bipiperidin-1′-yl]sulfonylcarbamate(Method L; 400 mg) and triethylamine (0.5 ml) in dichloromethane (5 ml)at ambient temperature were treated with 4-methylbenzoylchloride (163mg). The mixture was stirred overnight, the solvent was evaporated andthe residue was dissolved in DMSO (1 ml) and purified by HPLC (WatersXTerra® column) (acetonitrile/aqueous ammonia gradient) to give thetitle compound as a white solid (70 mg).

[0465] MS [M+H]⁺ (APCI+) 526/528 (M+H)

[0466]¹H NMR δ (DMSO) 1.51-1.61 (2H, m), 1.67-1.81 (2H, m), 1.86-1.96(2H, m), 1.98-2.08 (2H, m), 2.33 (3H, s), 2.71-2.92 (5H, m), 2.98-3.09(2H, m), 3.72 (2H, d), 4.52-4.61 (1H, m), 7.01 (1H, dd), 7.20 (2H, d),7.30 (1H, d), 7.52 (1H, d), 7.82 (2H, d).

[0467] The Examples 9B and 9C are examples of compounds of formula (Ib)and were prepared using similar methodology to that of Example 9A.

EXAMPLE 10A

[0468]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]4-methyl-benzenesulfonamide,Sodium Salt (an Example of a Compound of Formula (Ia)).

[0469] ToN-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide(0.05 g) was added 0.1M sodium hydroxide (0.949 ml) and methanol (5 ml).The solution was stirred until all of the starting material haddissolved. The solvent was removed under reduced pressure to give thetitle compound.

[0470] Mpt 201° C.

[0471] MS [M+H]⁺ (APCI+) 526/528

[0472]¹H NMR δ (CD₃OD) 1.28-1.42 (2H, m), 1.70-1.82 (4H, m), 1.96-2.04(2H, m), 2.35 (3H, s), 2.43-2.54 (3H, m), 2.56-2.66 (2H, m), 2.80-2.87(2H, m), 4.34-4.42 (3H, m), 6.87-6.90 (1H, m), 7.09-7.10 (1H, m),7.19-7.23 (2H, m), 7.35-7.38 (1H, m), 7.75-7.79 (2H, m).

[0473] The Examples 10B-10D are examples of compounds of formula (Ia)and were prepared using similar methodology to that of Example 10A.

EXAMPLE 11A

[0474]4-(3,4-Dichlorophenoxy)-N-[(1,2-dihydro-1-oxo-4-isoquinolinyl)carbonyl]-[1,4]-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

[0475] To a solution of1,1-dimethylethyl[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]sulfonyl]-carbamate(Method L; 0.305 g) in dichloromethane was added1,2-dihydro-1-oxo-4-isoquinolinecarbonyl chloride (0.147 g, preparedfrom the corresponding acid by treatment with thionyl chloride atreflux) followed by triethylamine (0.097 ml) and the reaction wasstirred under nitrogen for 12 h. The solvent was removed under reducedpressure with the resulting product dissolved in DMSO and purified byHPLC (Waters XTerra® column), (gradient, 75% aqueous (0.2%ammonia)/acetonitrile decreasing to 5% over 10 min) to give1,1-dimethylethyl[[4-(3,4dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]sulfonyl][(1,2-dihydro-1-oxo-4-isoquinolinyl)carbonyl]-carbamate.(MS [M+H]⁺ (ES+) 679/681).

[0476] 1,1-Dimethylethyl[[4-(3,4dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]sulfonyl][(1,2-dihydro-1-oxo-4-isoquinolinyl)carbonyl]-carbamatewas dissolved in dichloromethane (10 ml) followed by the addition oftrifluoroacetic acid, (3 ml) and allowed to stir under nitrogen for 12h. The solvent was removed under reduced pressure and the resultingproduct was dissolved in DMSO and purified by HPLC (Waters XTerra®column), (gradient, 90% aqueous (0.2% ammonia)/acetonitrile decreasingto 5% over 10 min) to give the title compound (0.028 g)

[0477] m.pt. 200° C.

[0478] MS [M+H]⁺ (ES+) 579/581

[0479]¹H NMR (399.98 MHz) δ (CD₃OD plus 1 drop NaOD) 1.58-1.69 (2H, m),1.71-1.81 (2H, m), 1.92-2.05 (4H, m), 2.37-2.46 (1H, m), 2.48-2.56 (2H,m), 2.76-2.90 (4H, m), 0.84-3.90 (2H, m), 4.35-4.42 (1H, m), 6.86-6.90(1H, m), 7.08 (1H, d), 7.30-7.34 (1H, m), 7.37 (1H, d), 7.49-7.54 (1H,m), 8.27-8.31 (1H, m), 8.44 (1H, s), 8.75 (1H, d)

EXAMPLE 12A

[0480]N-(Cyclohexylcarbonyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

[0481] To a solution of1,1-dimethylethyl[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]sulfonyl]-carbamate(Method L; 0.305 g) in chloroform was added cyclohexanecarbonyl chloride(0.094 ml), triethylamine (0.097 ml) and dimethylaminopyridine (0.086g). The reaction mixture was heated in a CEM Discover microwave at 300 Wfor 5 seconds reaching a temperature of 50° C.; pressure developed. Thesolvent was removed under reduced pressure and the resulting product wasdissolved in DMSO and purified by HPLC (Waters XTerra® column),(gradient, 90% aqueous (0.2% ammonia)/acetonitrile decreasing to 5% over10 min) to give the title compound (0.176 g) as a foam.

[0482] MS [M+H]⁺ (ES+) 518/520

[0483]¹H NMR (399.98 kHz) δ (CD₃OD) 1.10-1.38 (5H, m), 1.44-1.62 (3H,m), 1.65-1.76 (6H, m), 1.82-1.89 (2H, m), 1.90-1.98 (2H, m), 2.07-2.16(1H, m), 2.41-2.57 (3H, m), 2.72-2.86 (4H, m), 3.74-3.80 (2H, m),4.30-4.37 (1H, m), 6.78-6.81 (1H, m), 7.02 (1H, d), 7.28 (1H, d)

EXAMPLE 13A

[0484]4-(3,4-Dichlorophenoxy)-N-(2-methyl-1-oxopropyl)-[1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

[0485] To a solution of4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide (Method G;0.408 g) in dichloromethane (5 ml) was added 2-methyl-propanoyl chloride(0.126 ml), triethylamine (0.167 ml) and dimethylaminopyridine (0.147g). The reaction was heated in a CEM Discover microwave at 50° C. using50 W of power for 10 minutes. The solvent was removed under reducedpressure and the resulting product was dissolved in DMSO and purified byHPLC (Waters XTerra® column), (gradient, 90% aqueous (0.1% aqueousammonium acetate)/acetonitrile decreasing to 5% over 10 min) to give thetitle compound (0.152 g) as a foam.

[0486] MS [M+H]⁺ (ES+) 478/480

[0487]¹HNMR (399.98 MHz) δ (CD₃OD) 1.30 (6H, d), 1.75-1.91 (2H, m),1.97-2.11 (2H, m), 0.13-2.32 (4H, m), 2.65 (1H, septet), 2.77-2.99 (3H,m), 3.02-3.12 (2H, m), 3.12-3.25 (2H, m), 4.04-4.15 (2H, m), 4.62-4.72(1H, m), 7.09 (1H, dd), 7.31 (1H, d), 7.57 (1H, d)

EXAMPLE 14A

[0488]4-(3,4-Dichlorophenoxy)-N-(2-phenylacetyl)-[1,4′-bipiperidine]-1′-sulfonamide(an Example of a Compound of Formula (Ib)).

[0489] To a solution4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide (Method G;0.100 g) in THF (2 ml) was added potassium tert butoxide (0.083 g)followed after 1 h by phenylacetyl chloride (0.097 ml). After 12 h thesolvent was evaporated and the resultant product was dissolved inmethanol and loaded onto an Isolute® SCX cartridge which was washed withmethanol and eluted with 10% ammonia in methanol. The solvent wasevaporated and the residue was dissolved in DMSO and purified by HPLC(Waters XTerra® column), (gradient, 90% aqueous (0.2%ammonia)/acetonitrile decreasing to 75% over 10 min) to give the titlecompound (0.01 g).

[0490] MS [M+H]⁺ (ES+) 526/528

[0491]¹H NMR (299.945 MHz) δ (CD₃OD plus 1 drop NaOD) 1.45-1.59 (2H, m),1.70-1.89 (4H, m), 1.96-2.08 (2H, m), 2.23-2.35 (1H, m), 2.43-2.63 (4H,m), 2.77-2.88 (2H, m), 3.45 (2H, s), 3.66-3.75 (2H, m), 4.35-4.44 (1H,m), 6.88-6.94 (1H, m), 7.10-7.13 (1H, m), 7.14-7.30 (3H, m), 7.33-7.42(3H, m)

EXAMPLE 15A

[0492]N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-propanesulfonamide(an Example of a Compound of Formula (Ia)).

[0493] To a solution4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxamide (Method H;0.372 g) in THF (5 ml) was added potassium tert butoxide (0.337 g)followed after 1 h by 2-propanesulfonyl chloride (0.337 ml). After afurther 2 h aqueous ammonium chloride was added and THF was evaporatedto leave a precipitate which was collected. The precipitate was purifiedby HPLC (Waters XTerra® column), (gradient, 95% aqueous (0.2%ammonia)/acetonitrile decreasing to 50% over 10 min) to give the titlecompound (0.061 g).

[0494] MS [M+H]⁺ (ES+) 478/480

[0495]¹H NMR (399.98 MHz) δ (CD₃OD plus 1 drop NaOD) 1.19 (6H, d),1.23-1.37 (2H, m), 1.62-1.70 (2H, m), 1.71-1.78 (2H, m), 1.88-1.96 (2H,m), 2.34-2.47 (3H, m), 2.48-2.60 (2H, m), 2.72-2.80 (2H, m), 3.38-3.46(1H, m), 4.27-4.37 (3H, m), 6.79 (1H, dd), 6.99 (1H, d), 7.28 (1H, d)

EXAMPLE 16A

[0496]4-(3,4-Dichlorophenoxy)-N-[(4-methylphenyl)sulfonyl]-[1,4′-bipiperidine)-1′-sulfonamideSodium Salt (an Example of a Compound of Formula (Ie)).

[0497] 4-(3,4-Dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide(Method L; 582 mg), toluenesulfonyl chloride (380 mg) and DMAP (180 mg)were combined and dissolved in dichloromethane (10 ml). Triethylamine(0.3 ml) was added, followed after 35 min by a second portion oftriethylamine (0.3 ml). The solution was stirred for 21 h and thenconcentrated. The residue was triturated with methanol and then THF togive a solid (0.65 g). A portion of the product (0.34 g) was dissolvedin warm DMSO (30 ml). To this solution was added aqueous sodiumhydroxide (1M, 6 ml) followed by water (200 ml). The solution wasallowed to cool overnight and the title compound was collected (175 mg).

[0498] m. pt. 242-243° C.

[0499] MS [M+H]⁺ (ES+) 562/564

[0500]¹H NMR (399.98 MHz) δ (DMSO) 1.27 (2H, qd), 1.51-1.60 (2H, m),1.65 (2H, d), 1.88-1.94 (2H, m), 2.23 (1H, tt), 2.31 (3H, s), 2.32-2.43(4H, m), 2.68-2.75 (2H, m), 3.33-3.38 (2H, m), 4.37-4.43 (1H, m), 6.98(1H, dd), 7.18 (2H, d), 7.25 (1H, d), 7.48 (1H, d), 7.60 (2H, d)

[0501] Example 16B (an example of a compound of formula (Ie)) wasprepared using similar methodology to that of Example 16A andrecrystallisation was required after chromatography. MS [M + H]⁺ m. pt.Example Compound (ES+) ¹H NMR δ ° C. 1B N-[[4-(3,4- 526/528 (CD₃OD)1.18-1.30(m, 2H), 1.62-1.74(m, 4H); 1.87-1.95 228.1-228.6Recrystallisation Dichlorophenoxy)[1,4′- (m, 2H), 2.26(s, 3H),2.32-2.43(m, 3H), 2.48-2.57(m, solvent DMSO bipiperidin]-1′- 2H),2.70-2.76(m, 2H), 4.25-4.33(m, 3H), 6.77-6.81(m, yl]carbonyl]-4- 1H),6.98-7.00(m, 1H), 7.11-7.15(m, 2H), 7.28(d, 1H),methyl-benzenesulfonamide 7.65-7.68(m, 2H); 0.7 ml of CD₃OD plus 1 dropof NaOD (30% in D₂O) 1C N-[[4-(2,4-Dichloro-3- 540/542 (CD₃OD)1.50-1.61(m, 2H), 1.97-2.04(m, 2H), 2.08-2.21 methylphenoxy)[1,4′- (m,4H), 2.36(s, 3H), 2.47(s, 3H), 2.64-2.73(m, 2H), 3.22- bipiperidin]-1′-3.40(m, 5H), 4.40-4.49(m, 2H), 4.70-4.76(m, 1H), 7.01- yl]carbonyl]-4-7.03(m, 1H), 7.22-7.24(m, 2H), 7.27-7.29(m, 1H), 7.76-methyl-benzenesulfonamide 7.79(m, 2H). 1D 4-Chloro-N-[[4-(3,4-546/548/550 (CD₃OD) 1.18-1.28(m, 2H), 1.61-1.75(m, 4H), 1.87-1.94Recrystallisation dichlorophenoxy)[1,4′- (m, 2H), 2.33-2.43(m, 3H),2.47-2.58(m, 2H), 2.70-2.77 solvent methanol bipiperidin]-1′- (m, 2H),4.25-4.32(m, 3H), 6.78-6.80(m, 1H), 6.99-7.00 yl]carbonyl]- (m, 1H),7.27-7.34(m, 3H), 7.74-7.77(m, 2H); 0.7 ml of benzenesulfonamide CD₃ODplus 1 drop of NaOD(30% in D₂O) 1E N[[4-(3,4- 526/528 (CD₃OD)1.50-1.61(m, 2H), 2.01-2.11(m, 4H), 2.12-2.24 160-161Dichlorophenoxy)[1,4′- (m, 2H), 2.63-2.73(m, 2H), 2.64(s, 3H),3.25-3.43(m, bipiperidin]-1′- 5H), 4.43-4.52(m, 2H), 4.63-4.69(m, 1H),6.94-6.98(m, yl]carbonyl]-2- 1H), 7.20-7.25(m, 3H), 7.30-7.35(m, 1H),7.41-7.44(m, methyl-benzenesulfonamide 1H), 7.95-7.99(m, 1H) 1FN-[[4-(3,4- 512/514 (CD₃OD) 1.17-1.33(m, 2H), 1.59-1.76(m, 4H),1.86-1.96 207-214 Dichlorophenoxy)[1,4′- (m, 2H), 2.31-2.45(m, 3H),2.47-2.59(m, 2H), 2.69-2.78 bipiperidin]-1′- (m, 2H), 4.24-4.34(m, 3H),6.77-6.81(m, 1H), 6.98-7.00 yl]carbonyl]- (m, 1H), 7.26-7.36(m, 4H),7.76-7.81(m, 2H); plus 1 drop benzenesulfonamide of 30% NaOD 1GN-[[4-(4-Chloro-2- 506/508 (CD₃OD) 1.49-1.61(m, 2H), 1.99-2.05(m, 2H),2.06-2.14 methylphenoxy)[1,4′- (m, 2H), 2.15-2.23(m, 2H), 2.22(s, 3H),2.36(s, 3H), 2.64- bipiperidin]-1′- 2.73(m, 2H), 3.22-3.39(m, 5H),4.39-4.48(m, 2H), 4.60- yl]carbonyl]-4- 4.66(m, 1H), 6.91-6.95(m, 1H),7.10-7.17(m, 2H), 7.21- methyl-benzenesulfonamide 7.25(m, 2H),7.75-7.80(m, 2H) 1H N-[[4-(3,4- 546/548 (CD₃OD) 1.17-1.36(m, 2H),1.59-1.76(m, 4H), 1.85-1.97 Dichlorophenoxy)[1,4′- (m, 2H), 2.31-2.45(m,3H), 2.47-2.59(m, 2H), 2.68-2.78 bipiperidin]-1′- (m, 2H), 4.24-4.37(m,3H), 6.76-6.81(m, 1H), 6.98-7.00 yl]carbonyl]-2-chloro- (m, 1H),7.21-7.36(m, 4H), 7.94-8.01(m, 1H); plus 1 drop benzenesulfonamide of30% NaOD in D₂O 1I N-[[4-(2,4-Dichloro-3- 560/562/564 (CD₃OD)1.19-1.31(m, 2H), 1.68-1.79(m, 4H), 1.84- methylphenoxy)[1,4′- 1.93(m,2H), 2.35(s, 3H), 2.37-2.46(m, 3H), 2.48-2.58 bipiperidin]-1′- (m, 2H),2.71-2.79(m, 2H), 4.24-4.34(m, 2H), 4.35-4.41 yl]carbonyl]-4-chloro- (m,1H), 6.83-6.87(m, 1H), 7.14-7.17(m, 1H), 7.30-7.33 benzenesulfonamide(m, 2H), 7.74-7.77(m, 2H) 1 drop of 30% NaOD added in D₂O 1JN-[[4-[(3,4- 524/526 (CDCl₃) 7.79(3H, d), 7.32(1H, d), 7.20(2H, d),7.13(1H, 147-172 dichlorophenyl)methyl] d), 6.89(1H, dd), 4.56(2H, s),3.55(2H, d), 3.07(1H, s), 2.62 [1,4′-bipiperidin]- (4H, s), 2.35(5H, s),2.02(2H, d), 1.66(7H, d) 1′-yl]carbonyl]-4- methyl-benzenesulfonamide 1K2-Chloro-N[[4-[(3,4- 544/546/548 (CD₃OD) 8.07(1H, dd), 7.47-7.31(5H, m),7.09(1H, dd), 212-239 dichlorophenyl)methyl] 2.91(2H, d), 2.91(2H, d),2.59(2H, t), 2.52(2H, d), 2.43- [1,4′-bipiperidin]-1′- 2.34(1H, m),2.15(2H, t), 1.77(2H, d), 1.62(2H, d), 1.57- yl]carbonyl]- 1.44(1H, m),1.29(4H, d) benzenesulfonamide 1L 4-Chloro-N-[[4-[(3,4- 542/544/546(CD₃OD) 1.18-1.39(4H, m), 1.46-1.59(1H, m), 1.62(2H, 164-184dichlorophenyl)methyl] d), 1.77(2H, d), 2.15(2H, dd), 2.34-2.44(1H, m),2.49- [1,4′-bipiperidin]-1′- 2.65(4H, m), 2.90(2H, d), 4.34(2H, s),7.09(1H, dd), 7.32 yl]carbonyl]- (1H, d), 7.38-7.43(3H, m), 7.84(2H, dt)benzenesulfonamide 1M N-[[4-[(5-Chloro-2- 493/495 (DMSO) 8.20(1H, d),7.81(1H, dd), 7.67(2H, d), 7.23 (2H, pyridinyl)oxy][1,4′- d), 6.87(1H,d), 5.09-5.01(1H, m), 4.16(2H, d), 3.13-3.00 bipiperidin]-1′- (1H, m),2.94-2.77(1H, m), 2.62-2.53(5H, m), 2.33(3H, yl]carbonyl]-4- s),2.13-2.02(2H, m), 1.85-1.75(4H, m), 1.37-1.23(2H,methyl-benzenesulfonamide m) 1N 2-Chloro-N-[[4-(2- 530/532 (CD₃OD)1.44-1.56(m, 2H), 1.90-1.97(m, 2H), 1.98- chloro-4- 2.15(m, 4H),2.56-2.66(m, 2H), 3.20-3.40(m, 5H), fluorophenoxy)[1,4′- 4.35-4.46(m,2H), 4.54-4.64(m, 1H), 6.93-6.99(m, bipiperidin]-1′- 1H), 7.07-7.11(m,1H), 7.14-7.17(m, 1H), 7.24-7.35 yl]carbonyl]- (m, 3H), 7.99-8.02(m, 1H)benzenesulfonamide 1O N-[[4-(2-Chloro-4- 510/512 (CD₃OD) 1.27-1.37(m,2H), 1.78-1.87(m, 4H), 1.93- 221-222 fluorophenoxy)[1,4′- 2.02(m, 2H),2.35(s, 3H), 2.42-2.53(m, 3H), 2.57-2.67 bipiperidin]-1′- (m, 2H),2.82-2.89(m, 2H), 4.34-4.45(m, 3H), 6.97- yl]carbonyl]-4- 7.03(m, 1H),7.08-7.12(m, 1H), 7.16-7.20(m, 1H), methyl-benzenesulfonamide7.20-7.24(m, 2H), 7.74-7.77(m, 2H) 0.7 ml of CD3OD plus 1 drop ofNaOD(30% in D2O) 1P N-[[4-(2,4-Dichloro-3- ES + (CD₃OD) 1.42-1.53(m,2H), 1.89-1.95(m, 2H), 2.01- methylphenoxy)[1,4′- 526/ 528 2.09(m, 4H),2.37(s, 3H), 2.55-2.65(m, 2H), 3.17-3.34 bipiperidin]-1′- (m, 5H),4.32-4.41(m, 2H), 4.61-4.67(m, 1H), 6.91- yl]carbonyl]- 6.94(m, 1H),7.20-7.22(m, 1H), 7.30-7.37(m, 3H), benzenesulfonamide 7.78-7.82(m, 2H)1Q N-[[4-(4- 492/494 (CD₃OD plus 1 drop NaOD) 1.27-1.39(2H, m),1.70-1.84 237-238 chlorophenoxy)[1,4′- (4H, m), 1.96-2.04(2H, m),2.36(3H, s), 2.40-2.51, (3H, bipiperidin]-1′- m), 2.56-2.67(2H, m),2.79-2.87(2H, m), 4.31-4.42 yl]carbonyl]-4- (3H, m), 6.89(2H, d),7.20-7.24(4H, m), 7.76(2H, d) methyl- benzenesulfonamide 1RN-[[4-(2,4-dichloro-3- 540/542 (CD₃OD plus 1 drop NaOD) 1.27-1.41(2H,m), 1.78-1.88 methylphenoxy)[1,4′- (4H, m), 1.93-2.02(2H, m),2.44-2.55(3H, m), 2.44(3H, bipiperidin]-1′- s), 2.57-2.67(2H, m),2.66(3H, s), 2.81-2.89(2H, m), yl]carbonyl]-2- 4.35-4.51(3H, m),6.95(1H, d), 7.19-7.34(4H, m), 7.94- methyl-benzenesulfonamide 7.97(1H,m) 1S N-[[4-(2,4-dichloro-3- (CDCl₃) 1.61(2H, q), 2.07(4H, t), 2.28(2H,t), 2.38(3H, s), fluorophenoxy)[1,4′- 2.70(2H, t), 2.93-3.05(1H, m),3.12(2H, t), 3.18-3.28 bipiperidin]-1′- (2H, m), 4.45(2H, d),4.60-4.67(1H, m), 6.79(1H, dd), yl]carbonyl]-4- 7.24(2H, d), 7.30(1H,d), 7.80(2H, d) methyl-benzenesulfonamide 1T N-[[4-(4-chloro-2- 506/508(CD₃OD) 1.40-1.55(3H, m), 1.91-2.03(6H, m), 2.13(3H, 161methylphenoxy)[1,4′- s), 2.56(3H, s), 2.56-2.64(3H, m), 3.23-3.30(3H,m), bipiperidin]-1′- 4.34-4.44(2H, m), 4.50-4.56(1H, m), 6.80(1H, d),7.00- yl]carbpnyl]-2- 7.07(2H, m), 7.11-7.16(2H, m), 7.20-7.25(1H, m),7.84- methyl-benzenesulfonamide 7.88(1H, m) 1U 2-chloro-N-[[4-(4-526/528 (CD₃OD) 1.51-1.64(3H, m), 2.05(5H, d), 2.71(3H, t), 164chloro-2- 3.33-3.40(4H, m), 4.44-4.56(3H, m), 4.61-4.68(2H,methylphenoxy)[1,4′- m), 6.94(1H, d), 7.12(1H, dd), 7.34(1H, d),7.35(1H, d), bipiperidin]-1′- 7.38(1H, dd), 7.42-7.45(1H, m), 8.09(1H,dd) yl]carbonyl] benzenesulfonamide 1V 4-chloro-N-[[4-(4- 526/528(CD₃OD) 1.68-1.82(2H, m), 2.09-2.15(4H, m), 2.17- 160 chloro-2- 2.21(3H,m), 2.37-2.48(2H, m), 2.59-2.71(2H, m), 2.99- methylphenoxy)[1,4′-3.14(3H, m), 3.40-3.52(2H, m), 4.49-4.63(3H, m), bipiperidin]-1′-6.68(1H, d), 7.07-7.16(2H, m), 7.36(2H, d), 7.88(2H, d) yl]carbonyl]-benzenesulfonamide 1W N-[[4-(2,4- 526/528 (CD₃OD plus 1 drop NaOD)1.27-1.40(2H, m), 1.77-1.88 dichlorophenoxy)[1,4′- (4H, m),1.94-2.03(2H, m), 2.35(3H, s), 2.42-2.55(3H, bipiperidin]-1′- m),2.56-2.68(2H, m), 2.80-2.88(2H, m), 4.33-4.44 yl]carbonyl]-4- (2H, m),4.45-4.52(1H, m), 7.08(1H, d), 7.21-7.25(3H, methyl-benzenesulfonamidem), 7.38(1H, d), 7.76(2H, d) 1X N-[[4-(3- 492/494 (CD₃OD plus 1 dropNaOD) 1.30(2H, q), 1.71-1.83(4H, 172-178 chlorophenoxy)[1,4′- m),1.94-2.04(2H, m), 2.34(3H, s), 2.40-2.50(3H, m), bipiperidin]-1′-2.56-2.68(2H, m), 2.75-2.83(2H, m), 4.32-4.43(3H, yl]carbonyl]-4- m),6.81-6.89(3H, m), 7.22(1H, t), 7.22(2H, d), 7.76(2H, d) methyl-benzenesulfonamide 1Y 2-chloro-N-[[4-(3- 512/514 (CD₃OD plus 1 dropNaOD) 1.30-1.43(2H, m), 1.72-1.86 180-186 chlorophenoxy)[1,4′ (4H, m),1.97-2.03(2H, m), 2.42-2.53(3H, m), 2.58- bipiperidin]-1′- 2.67(2H, m),2.80-2.87(2H, m), 4.35-4.46(3H, m), 6.85- yl]carbonyl]- 6.94(3H, m),7.22(1H, t), 7.32-7.46(3H, m), 8.08(1H, dd) benzenesulfonamide 1ZN-[[4-(3- 478/480 (CD₃OD plus 1 drop NaOD) 1.26-1.41(2H, m), 1.69-1.85197-206 chlorophenoxy)[1,4′- (4H, m), 1.95-2.04(2H, m), 2.41-2.53(3H,m), 2.57- bipiperidin]-1′- 2.68(2H, m), 2.79-2.88(2H, m), 4.34-4.46(3H,m), 6.83- yl]carbonyl]- 6.94(3H, m), 7.22(1H, dt), 7.39-7.46(3H, m),7.87-7.89 benzenesulfonamide (2H, m) 1AA 2-chloro-N-[[4-(3- 526/528(CD₃OD plus 1 drop NaOD) 1.32-1.43(2H, m), 1.76-1.86 223-234 chloro-2-(4H, m), 1.95-2.04(2H, m), 2.25(3H, s), 2.46-2.55(3H,methylphenoxy)[1,4′- m), 2.59-2.69(2H, m), 2.79-2.87(2H, m), 4.35-4.48bipiperidin]-1′- (3H, m), 6.88(1H, d), 6.93(1H, d), 7.08(1H, t),7.32-7.45 yl]carbdnyl]- (3H, m), 8.08(1H, dd) benzenesulfonamide 1ABN-[[4-(2-chloro-4- 510/512 (DMSO) 1.17-1.46(2H, m), 1.65-2.16(8H, m),2.57 (3H, s), 164-165 fluorophenoxy)[1,4′- 2.77-3.85(6H, m),4.12-4.32(2H, m), 7.12-7.34(5H, m), bipiperidin]-1′- 7.46(1H, dd),7.78(1H, d) yl]carbonyl]-2- methyl-benzenesulfonamide 1AC2-chloro-N-[[4-(2,4- 564/566/568 (DMSO) 1.20-1.50(2H, m), 1.69-2.30(7H,m), 2.88- 172-173 dichloro-3- 3.60(8H, m), 4.17-4.40(1H, m),7.10-7.27(1H, m), 7.27- fluorophenoxy)[1,4′- 7.44(3H, m), 7.57(1H, t),7.83-7.98(1H, m) bipiperidin]-1′- yl]carbonyl]- benzenesulfonamide 1AD4-chloro-N-[[4-(2,4- 564/566/568 (DMSO) 1.21-1.48(2H, m), 1.64-2.25(6H,m), 2.88- 167-168 . dichloro-3- 3.40(9H, m), 4.10-4.41(1H, m), 7.18(1H,dd), 7.43(2H, fluorophenoxy)[1,4′- d), 7.56(1H, t), 7.67-7.85(2H, d)bipiperidin]-1′- yl]carbonyl]- benzenesulfonamide 1AEN-[[4-(2,4-dichloro-3- 544/546 (DMSO) 1.21-1.42(2H, m), 1.62-2.17(6H,m), 2.55(3H, 151-152 fluorophenoxy)[1,4′- s), 2.75-3.24(7H, m),4.09-4.35(2H, m), 4.60-4.87(1H, bipiperidin]-1′- m), 7.13-7.24(3.H, m),7.28-7.37(1H, m), 7.55(1H, t), yl]carbonyl]-2- 7.80(1H, d)methyl-benzenesulfonamide 1AF 2-chloro-N-[[4-(4- 512/514 (DMSO)1.23-1.53(2H, m), 1.62-2.39(7H, m), 2.92- 182-183 chlorophenoxy)[1,4′-3.68(6H, m), 4.13-4.44(2H, m), 4.44-4.91(1H, m), 6.95- bipiperidin]-1′-7.17(2H, m), 7.30-7.45(5H, m), 7.82-8.01(1H, m) yl]carbonyl]-benzenesulfonamide 1AH 4-chloro-N-[[4-(4- 512/514 (DMSO) 1.11-1.37(3H,m), 1.47-2.20(7H, m), 2.55- 249-250 chlorophenoxy)[1,4′- 3.24(6H, m),4.04-4.64(2H, m), 7.00(2H, d), 7.32(2H, d), bipiperidin]-1′- 7.39(2H,dt), 7.72(2H, dt) yl]carbonyl]- benzenesulfonamide 1AI N-[[4-(4- 492/494(DMSO) 1.14-1.43(2H, m), 1.64-2.16(6H, m), 2.55(3H, 153-154chlorophenoxy)[1,4′- s), 2.77-3.52(7H, m), 4.15-4.32(2H, m),4.42-4.71(1H, bipiperidin]-1′- m), 7.02(2H, d), 7.12-7.25(2H, m),7.25-7.39(3H, m), yl]carbonyl]-2- 7.78(1H, d) methyl-benzenesulfonamide1AJ 2-chloro-N-[[4-(2,4- 546/548/550 (DMSO) 1.22-1.49(2H, m),1.65-2.27(6H, m), 2.94- 162-163 dichlorophenoxy)[1,4′- 3.62(8H, m),4.15-4.43(2H, m), 7.20-7.47(5H, m), 7.62 bipiperidin]-1′- (1H, s),7.83-8.02(1H, m) yl]carbonyl]- benzenesulfonamide 1AK4-chloro-N-[[4-(2,4- 546/548/550 (DMSO) 1.14-1.50(2H, m), 1.66-2.23(6H,m), 2.83- 169-170 dichlorophenoxy)[1,4′- 3.48(9H, m), 4.19-4.31(1H, m),7.29(2H, d), 7.36-7.45 bipiperidin]-1′- (2H, m), 7.61(1H, d)7.68-7.88(2H, m) yl]carbonyl] benzenesulfonamide. 1AL N-[[4-(2,4-526/528 (CD₃OD) 1.73-2.06(6H, m), 2.42-2.63(6H, m), 2.66(3H, 165-166dichlorophenoxy)[1,4′- s), 2.78-2.92(3H, m), 4.35-4.54(3H, m), 7.08(1H,d), bipiperidin]-1′- 7.19-7.26(3H, m), 7.28-7.34(1H, m), 7.39(1H, d),7.91- yl]carbonyl]-2- 8.02(1H, m) methyl-benzenesulfonamide 1AM2-chloro-N-[[4-(3,4- 514/516 (DMSO) 1.28-1.47(2H, m), 1.59-2.40(6H, m),2.90- 165-166 difluorophenoxy)[1,4′- 3.60(7H, m), 4.16-4.42(2H, m),4.44-4.92(1H, m), 6.77- bipiperidin]-1′- 6.92(1H, m), 7.07-7.45(5H, m),7.81-7.98(1H, m) yl]carbonyl]- benzenesulfonamide 1AN N-[[4-(3,4- 494(DMSO) 1.20-1.48(2H, m), 1.56-2.27(6H, m), 2.55(3H, 147-148difluorophenoxy)[1,4′- s), 2.86-3.57(8H, m), 4.04-4.64(2H, m),6.77-6.90(1H, bipiperidin]-1′- m), 7.11-7.46(5H, m), 7.75-7.88(1H, d)yl]carbonyl]-2- methyl-benzenesulfonamide 1AO N-[[4-(3,4- 494 (DMSO)1.18-1.44(2H, m), 1.57-2.20(6H, m), 2.53(3H, 140-141difluorophenoxy)[1,4′- s), 2.63-3.53(7H, m), 4.11-4.23(2H, m),4.38-4.67(1H, bipiperidin]-1′- m), 6.78-6.85(1H, m), 7.09-7.18(1H, m),7.22(2H, d), yl]carbonyl]-4- 7.34(1H, dd), 7.67(2H, d)methyl-benzenesulfonamide 1AP N-[[4-(3-chloro-2- 506/508 (CD₃OD plus 1drop NaOD) 1.23-1.36(2H, m), 1.80(4H, 206-210 methylphenoxy)[1,4′- d),1.93-2.03(2H, m), 2.22(3H, s), 2.32(3H, s), 2.42-2.52 bipiperidin]-1′-(3H, m), 2.58-2.67(2H, m), 2.73-2.80(2H, m), 4.33- yl]carbonyl]-4-4.45(3H, m), 6.84(1H, d), 6.90(1H, d), 7.08(1H, t), 7.21methyl-benzenesulfonamide (2H, d), 7.76(2H, d) 1AQ N-[[4-(3-chloro-2-492/494 (CD₃OD plus 1 drop NaOD) 1.28-1.45(2H, m), 1.79-1.89 173-186methylphenoxy)[1,4′- (4H, m), 1.97-2.08(2H, m), 2.26(3H, s),2.42-2.70(5H, bipiperidin]-1′- m), 2.79-2.89(2H, m), 4.37-4.48(3H, m),6.89(1H, d), yl]carbonyl]- 6.94(1H, d), 7.09(1H, td), 7.39-7.47(3H, m),7.87-7.92 benzenesulfonainide (2H, m) 1AR 3-chloro-N-[[4-(3,4-546/548/550 (CD₃OD) 1.23-1.44(4H, m), 1.70-1.87(4H, m), 1.99(2H, 145-155dichlorophenoxy)[1,4′- s), 2.49(2H, d), 2.56-2.70(1H, m), 2.83(2H, s),4.38(3H, bipiperidin]-1′- s), 6.88(1H, dd), 7.09(1H, d), 7.33-7.45(3H,m), 7.79 yl]carbonyl]- (1H, dd), 7.88(1H, d) benzenesulfonamide 1ASN-[[4-(2,4-dichloro-3- 544/546 (CD₃OD) 1.58(2H, td), 2.00-2.08(2H, m),2.16(4H, d), 147-169 methylphenoxy)[1,4′- 2.46(3H, s), 2.70(2H, t),3.32-3.46(4H, m), 4.46(2H, d), bipiperidin]-1′- 4.58(1H, s), 4.74(1H,s), 7.03(1H, d), 7.14(2H, t), 7.30 yl]carbonyl]-4-fluoro- (1H, d),7.88-7.94(2H, m) benzenesulfonamide 1AT 2-chloro-N-[[4-(2,4- 560/562/564(CD₃OD plus 1 drop NaOD) 1.28-1.45(2H, m), 1.77-1.88 216 dichloro-3-(4H, m), 1.94-2.02(2H, m), 2.45(3H, s), 2.46-2.56(3H,methylphenoxy)[1,4′- m), 2.58-2.68(2H, m), 2.82-2.89(2H, m), 4.36-4.51bipiperidin]-1′- (3H, m), 6.95(1H, d), 7.25(1H, d), 7.32-7.44(3H, m),8.08- yl]carbonyl]- 8.11(1H, m) benzenesulfonamide 1AUN-[[4-(3,4-dichloro-2- 540/2 (CD₃OD plus 1 drop NaOD) 1.28-1.41(2H, m),1.76-1.85 195-200 methylphenoxy)[1,4′- (4H, m), 1.96-2.05(2H, m),2.31(3H, s), 2.35(3H, s), 2.43- bipiperidin]-1′- 2.56(3H, m),2.57-2.67(2H, m), 2.77-2.85(2H, m), yl]carbonyl]-4- 4.34-4.47(3H, m),6.91(1H, d), 7.22(2H, d), 7.27(1H, d), methyl-benzenesulfonamide7.76(2H, d) 1AV 2-chloro-N-[[4-(3,4- 560/562/564 171 dichloro-2-methylphenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]- benzenesulfonamide2B 3-Cyano-N[[4-(3,4- 537/539 (CD₃OD) 1.27-1.40(m, 2H), 1.70-1.85(m,4H), 1.96- dichlorophenoxy)[1,4′- 2.04(m, 2H), 2.43-2.53(m, 3H),2.56-2,69(m, 2H), 2.79- bipiperidin]-1′- 2.86(m, 2H), 4.33-4.42(m, 3H),6.86-6.90(m, 1H), yl]carbonyl]- 7.07-7.09(m, 1H), 7.36-7.39(m, 1H),7.59-7.64(m, benzenesulfonamide 1H), 7.78-7.81(m, 1H), 8.13-8.16(m, 1H),8.21-8.22 (m, 1H); plus 1 drop of NaOD, 30% in D₂O 2C N-[[4-(3,4-580/582 (CD₃OD) 1.40-1.53(m, 2H), 1.91-1.97(m, 4H), 2.01- 170-180dichlorophenoxy)[1,4′- 2.16(m, 2H), 2.55-2.65(m, 2H), 3.17-3.36(m, 5H),4.33- bipiperidin]-1′- 4.42(m, 2H), 4.55-4.62(m, 1H), 6.84-6.89(m, 1H),yl]carbonyl]-3- 7.11-7.13(m, 1H), 7.33(d, 1H), 7.51-7.56(m, 1H), 7.63-(trifluoroniethyl)- 7.67(m, 1H), 8.02-8.05(m, 1H), 8.09(s, 1H)benzenesulfonamide 2D N-[[4-(3,4- 542/544 (CD₃OD plus 1 drop NaOD)1.28-1.40(2H, m), 1.70-1.84 dichlorophenoxy)[1,4′- (4H, m),1.96-2.04(2H, m), 2.42-2.53(3H, m), 2.56- bipiperidin]-1′- 2.66(2H, m),2.78-2.86(2H, m), 3.81(3H, s), 4.34-4.42 yl]carbonyl]-4- (3H, m),6.87-6.90(1H, m), 6.91-6.95(2H, m), 7.09(1H, methoxy-benzenesulfonamided), 7.37(1H, d), 7.79-7.83(2H, m) 2E N-[[4-(3,4- 566/568 (CD₃OD plus 1drop NaOD) 1.28-1.43(2H, m), 1.70-1.85 223-228 dichlorophenoxy)[1,4′-(4H, m), 1.96-2.05(2H, m), 2.43-2.54(3H, m), 2.57- bipiperidin]-1′-2.69(2H, m), 2.80-2.88(2H, m), 4.33-4.43(3H, m), 6.88yl]carbonyl]-2,4,5- (1H, dd), 7.09(1H, d), 7.20(1H, ddd), 7.37(1H, d),7.79 trifluoro- (1H, ddd) benzenesulfonamide 2F N-[[4-(3,4- 548/550(CD₃OD) 1.51-1.63(2H, m), 2.00-2.09(4H, m), 2.09- 212-222dichlorophenoxy)[1,4′- 2.27(3H, m), 2.65-2.76(2H, m), 3.32-3.46(4H, m),4.41- bipiperidin]-1′- 4.54(2H, m), 4.63-4.73(1H, m), 6.97(1H, dd),7.12- yl]carbonyl]-2,5- 7.24(3H, m), 7.43(1H, d), 7.59-7.63(1H, m)difluoro- benzenesulfonamide 2G N-[[4-(3,4- 555/557 (CD₃OD plus 1 dropNaOD) 1.25-1.34(2H, m), 1.66-1.77 194-196 dichlorophenoxy)[1,4′- (4H,m), 1.94-2.02(2H, m), 2.39-2.47(3H, m), 2.52- bipiperidin]-1′- 2.61(2H,m), 2.75-2.83(2H, m), 2.97(6H, s), 4.31-4.43 yl]carbonyl]-4- (3H, m),6.67-6.70(2H, m), 6.93(1H, dd), 7.14(1H, d), (dimethylamino)- 7.42(1H,d), 7.64-7.68(2H, m) benzenesulfonamide 2H N-[[4-(3,4- 542/544 (CD₃OD)1.28-1.41(2H, m), 1.71-1.84(4H, m), 1.96- 215-218 dichlorophenoxy)[1,4′-2.04(2H, m), 2.42-2.53(3H, m), 2.57-2.66(2H, m), 2.80- bipiperidin]-1′-2.87(2H, m), 3.89(3H, s), 4.35-4.44(3H, m), 6.88(1H, yl]carbonyl]-2-dd), 6.94-6.99(1H, m), 7.05-7.10(2H, m), 7.37(1H, d),methoxy-benzenesulfonamide 7.40-7.44(1H, m), 7.87(1H, dd) 2I4-bromo-N-[[4-(3,4- 590/592/594 220-223 dichlorophenoxy)[1,4′-bipiperidin]-1′- yl]carbonyl]- benzenesulfonamide 2J 3,5-dichloro-N-[[4-580/582/584 (3,4- dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-benzenesulfonamide 2K Methyl 2-[[[[4-(3,4- 570/572dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]amino]sulfonyl]-benzoate 2L 2-bromo-N-[[4-(3,4- 590/592/594 dichlorophenoxy)[1,4′-bipiperidin]-1′- yl]carbonyl]- benzenesulfonamide 2M5-chloro-N-[[4-(3,4- 552/554/556 dichlorophenoxy)[1,4′- bipiperidin]-1′-yl]carbonyl]-2- thiophenesulfonamide 2N 4,5-dichloro-N-[[4- 586/588/590(3,4- dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-2-thiophenesulfonamide 2O 4-chloro-N-[[4-(3,4- 574/576/578dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-2,5- dimethyl-benzenesulfonamide 2P 2,5-dichloro-N-[[4- 586/588/590 (3,4-dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-3-thiophenesulfonamide 2Q N-[[4-(3,4- 596/598 dichlorophenoxy)[1,4′-bipiperidin]-1′- yl]carbonyl]-2- (trifluoromethoxy)- benzenesulfonamide2R 4-bromo-N-[[4-(3,4- 596/598/600 dichlorophenoxy)[1,4′-bipiperidin]-1′- yl]carbonyl]-2- thiophenesulfonamide 2S N-[[4-(3,4-596/598 dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-4-(trifluoromethoxy)- benzenesulfonamide 2T 5-chloro-N-[[4-(3,4-582/584/586 dichlorophenoxy) [1,4′- bipiperidin]-1′- yl]carbonyl]-2,4-difluoro- benzenesulfonamide 2U 4-chloro-N-[[4-(3,4- 582/584/586dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-2,5- difluoro-benzenesulfonamide 2V 3-chloro-N-[[4-(3,4- 578/580/582dichlorophenoxy)[1,4′- bipiperidin]-1′- yl]carbonyl]-5-fluoro- 2-methyl-benzenesulfonamide 2X N-[[4-(3,4- 540/542 (CD₃OD plus 1 drop NaOD)1.53(2H, dd), 1.98-2.24(7H, dichlorophenoxy)[1,4′- m), 2.63-2.74(2H, m),2.72(6H, s), 3.20-3.39(4H, m), bipiperidin]-1′- 4.43(2H, d),4.63-4.69(1H, m), 6.96(1H, dd), 7.05(2H, yl]carbonyl]-2,6- d), 7.14(1H,dd), 7.21(1H, d), 7.42(1H, d) dimethyl- benzenesulfonamide 2YN-[[4-(3,4- 555/557 (CD₃OD plus 1 drop NaOD) 1.27-1.42(2H, m), 1.70-1.86dichlorophenoxy)[1,4′- (4H, m), 1.96-2.05(2H, m), 2.41-2.54(3H, m),2.57- bipiperidin]-1′- 2.67(2H, m), 2.73(6H, s), 2.80-2.88(2H, m),4.35-4.47 yl]carbonyl]-2- (3H, m), 6.88(1H, dd), 7.08-7.14(2H, m),7.30-7.43(3H, (dimethylamino)- m), 7.98(1H, dd) benzenesulfonamide 2ZN-[[4-(3,4- 555/557 (DMSO) 1.15(3H, t), 1.20-1.28(2H, m), 1.53-1.63(2H,dichlorophenoxy)[1,4′- m), 1.65-1.72(2H, m), 1.88-1.96(2H, m), 2.37-2.47bipiperidin]-1′- (3H, m), 2.57-2.68(2H, m), 2.70-2.79(2H, m), 3.08(2H,yl]carbonyl]-4- dt), 3.94-4.01(2H, m), 4.39-4.47(1H, m), 6.38-6.43(ethylamino)- (1H, m), 6.53-6.58(2H, m), 6.97(1H, m), 7.25(1H, d),benzenesulfonamide 7.48-7.51(1H, m), 7.53-7.57(2H, m) 5B N-Benzoyl-4-(4-492/494 (CD₃OD) 1.57-1.73(m, 2H), 1.75-1.88(m, 2H), 1.90- 237-238chloro-2- 2.07(m, 4H), 2.19(s, 3H), 2.37-2.49(m, 1H), 2.50-2.61methylphenoxy)-[1,4′- (m, 2H), 2.73-2.91(m, 4H), 3.80-3.90(m, 2H), 4.36-bipiperidine]-1′- 4.45(m, 1H), 6.87-6.91(m, 1H), 7.07-7.13(m, 2H), 7.32-sulfonamide 7.46(m, 3H), 8.04(d, 2H); (plus 1 drop of 30% NaOD in D₂O)5C N-Benzoyl-4-[(3,4- 510/512 (CD₃OD) 8.00(2H, dt), 7.43-7.37(2H, m),7.36-7.29(3H, 193-196 dichlorophenyl)methyl]- m), 7.09(1H, dd), 3.81(2H,d), 2.94(2H, d), 2.74(2H, t), [1,4′-bipiperidine]- 2.53(2H, d), 2.35(1H,t), 2.18(2H, t), 1.89(3H, s), 1.67- 1′-sulfonamide 1.48(5H, m),1.33-1.21(2H, m) 5D N-benzoyl-4-(3,4- 526/528 (CD₃OD plus 1 drop NaOD)1.58-1.70(2H, m), 1.76-1.86 198-199 dichloro-2- (2H, m), 1.90-1.96(2H,m), 1.97-2.05 (2H, m), 2.31(3H, methylphenoxy)-[1,4′- s), 2.38-2.47(1H,m), 2.51-2.58(2H, m), 2.74-2.88(4H, bipiperidine]-1′- m), 3.81-3.87(2H,m), 4.40-4.47(1H, m), 6.91(1H, d), sulfonamide 7.27(1H, d),7.31-7.36(2H, m), 7.38-7.43(1H, m), 8.00- 8.03 (2H, m) 5EN-benzoyl-4-(2,4- 512/514 (CD₃OD plus 1 drop NaOD) 1.58-1.70(2H, m),1.79-1.88 233-235 dichlorophenoxy)- (2H, m); 1.90-2.04(4H, m),2.38-2.47(1H, m), 2.51- [1,4-bipiperidine]-1′- 2.58(2H, m),2.74-2.82(2H, m), 2.84-2.92(2H, m), 3.81- sulfonamide 3.87(2H, m),4.45-4.52(1H, m), 7.08(1H, d), 7.23(1H, dd), 7.31-7.36(2H, m),7.39-7.43(2H, m), 8.00-8.03 (2H, m) 6B trans N-[[4-[4-(3,4- 525/527(CD₃OD) 1.33(4H, d), 1.66-1.79(2H, m), 1.83-2.12(7H, dichlorophenoxy)-1-m), 2.25-2.37(1H, m), 2.50(2H, s), 2.64(3H, s), 2.78-piperidinyl]cyclohexyl] 2.89(2H, m), 4.32-4.40(1H, m), 6.87(1H, dd),7.08(1H, carbonyl]-2-methyl- d), 7.22(2H, d), 7.30-7.34(1H, m), 7.36(1H,d), 7.98(1H, d) benzenesulfonamide 6C trans N-[[4-[4-(3,4- 541/543(CD₃OD) 1.27-1.45(4H, m), 1.70-1.81(2H, m), 1.85- dichlorophenoxy)-1-2.19(7H, m), 2.24-2.39(1H, m), 2.45-2.58(2H, m), 2.80-piperidinyl]cyclohexyl] 2.91(2H, m), 3.89(3H, s), 4.33-4.44(1H, m),6.85-7.13 carbonyl]-2- (4H, m), 7.35-7.50(2H, m), 7.87-7.92(1H, m)methoxy-benzenesulfonamide 6D trans N-[[4-[4-(3,4- 539/541 (CD₃OD)1.34(4H, d), 1.64-1.80(2H, m), 1.85-2.14(7H, dichlorophenoxy)-1- m),2.25-2.37(1H, m), 2.45-2.57(2H, m), 2.73(6H, s), piperidinyl]cyclohexyl]2.80-2.90(2H, m), 4.32-4.41(1H, m), 6.85-6.92(1H, carbonyl]-2,6- m),7.00-7.21(4H, m), 7.38(1H, d) dimethyl-benzenesulfonamide 6E transN-[[4[[4-(3,4- 525/527/529 (CD₃OD plus 1 drop NaOD) 1.26-1.41(4H, m),1.72-1.82 dichlorophenoxy)-1- (2H, m), 1.88-2.13(7H, m), 2.28-2.37(1H,m), 2.40(3H, piperidinyl]cyclohexyl] s), 2.53(2H, s), 2.86(2H, s),4.40(1H, s), 6.90(1H, dd), carbonyl]-4-methyl- 7.11(1H, d), 7.27(2H, d),7.39(1H, d), 7.79(2H, d); benzenesulfonamide 6F trans N-[[4-[4-(3,4-511/513/515 (CD₃OD plus 1 drop NaOD) 6.78(1H, d), 6.99(1H, d), 7.27dichlorophenoxy)-1- (1H, d), 7.30-7.38(3H, m), 7.76-7.83(2H, m)piperidinyl]cyclohexyl] (of aromatic region only) carbonyl]-benzenesulfonamide 6G tarns N-[[4-[4-(3,4- 554/556/558 (CD₃OD plus 1drop NaOD) 1.27-1.46(4H, m), 1.71-1.85 dichlorophenoxy)-1- (2H, m),1.88-2.12(7H, m), 2.31-2.40(1H, m), 2.53(2H, piperidinyl]cyclohexyl] t),2.86(2H, d), 3.03(6H, s), 4.36-4.45(1H, m), 6.73(2H, carbonyl]-4- d),6.91(1H, dd), 7.11(1H, d), 7.40(1H, d), 7.74(2H, d) (dimethylamino)-benzenesulfonamide 8B N-(3-cyanobenzoyl)- 537/539 (DMSO) 1.55-1.80(4H,m), 1.92-2.18(6H, m), 2.63- 254-255 4-(3,4- 2.75(2H, m), 3.00-3.26(4H,m), 3.59-3.77(2H, m), 6.96- dichlorophenoxy)-[1,4- 7.11(1H, m),7.29-7.41(1H, m), 7.44-7.63(2H, m), bipiperidine]-1- 7.85(1H, d),8.21(2H, dt) sulfonamide 8C 4-(3,4- 530/532 (DMSO) 1.55-1.80(3H, m),1.92-2.18(6H, m), 2.63- 141-1431 dichlorophenoxy)-N- 2.75(2H, m),3.00-3.26(4H, m), 3.59-3.77(2H, m) 3.59- (4-fluorobenzoyl)-[1,4′-3.78(1H, m), 6.89-7.24(3H, m), 7.33(1H, s), 7.53(1H, bipiperidine]-1′-d), 7.96(2H, dd) sulfonamide 8D 4-(3,4- 590/592 (DMSO) 1.46-2.20(10H,m), 2.62-2.80(6H, m), 3.24 244-246 dichlorophenoxy)-N-[3- (3H, s),3.66-3.76(2H, m), 7.04(1H, s), 7.35(1H, s), 7.54(methylsulfonyl)benzoyl]- (1H, d), 7.62(1H, t), 7.95(1H, d), 8.23(1H,dt), 8.42(1H, t) [1,4′-bipiperidine]- 1′-sulfonainide 8E 4-(4-chloro-2-570/572 (DMSO) 1.51-1.79(4H, m), 1.91-2.24(8H, m), 2.64- 235-236methylphenoxy)-N-[3- 2.75(3H, m), 3.20(3H, s), 3.66-3.75(2H, m),4.43-4.81 (methylsulfonyl)benzo (1H, m), 6.98-7.05(1H, m), 7.19(1H, dd),7.24(1H, d), yl]-[1,4-bipiperidine]- 7.62(1H, t), 7.94(1H, d), 8.23(1H,dt), 8.42(1H, t) 1′-sulfonamide 8F N-(2-chlorobenzoyl)- 546/548/550(DMSO) 1.44-1.73(4H, m), 1.86-2.17(6H, m), 2.63- 187-1884-(3,4-dichlorophenoxy)- 2.77(2H, m), 3.03-3.16(4H, m), 3.64-3.72(2H,m), 7.03 [1,4-bipiperidine]-1′- (1H, d), 7.32-7.42(3H, m), 7.54(1H, d),7.92(2H, dt) sulfonamide 8G N-(4-chlorobenzoyl)- 546/548/550 (DMSO)0.92-2.22(11H, m), 2.57-2.78(6H, m), 3.63- 156-1574-(3,4-dichlorophenoxy)- 3.77(1H, m), 7.03(1H, d), 7.31-7.41(3H, m),7.54(1H, d), [1,4′-bipiperidine]-1′- 7.92(2H, dd) sulfonamide 8HN-(4-chlorobenzoyl)- 526/528 (DMSO) 1.02-1.61(4H, m), 1.63-2.03(3H, m),2.13- 138-139 4-(4-chloro-2- 2.19(2H, m), 2.52(3H, s), 2.56-2.69(3H, m),2.97-3.14 methylphenoxy)-[1,4′- (4H, m), 3.52-3.78(2H, m), 7.00(1H, d),7.16(1H, dd), bipiperidine]-1′- 7.22(1H, d), 7.32-7.39(2H, m), 7.91(2H,dt) sulfonamide 9B 4-(3,4- 542/544 (DMSO) 0.95-1.31(3H, m),1.31-1.96(6H, m), 2.24(3H, 202-203 dichlorophenoxy)-N- s), 2.57-2.75(7H,m), 3.55-3.73(2H, m), 6.95-7.05(2H, (2-methoxybenzoyl)- m), 7.13(1H, d),7.26(1H, d), 7.47(3H, dd) [1,4′-bipiperidine]-1′- sulfonamide 9C 4-(3,4-542/544 (DMSO) 1.40-2.19(6H, m), 2.70-2.89(5H, m), 2.95- 142-143dichlorophenoxy)-N- 3.13(2H, m), 3.68-3.79(4H, m), 3.87(3H, s),4.43-4.66 (4-methoxybenzoyl)- (1H, m), 6.95(2H, d), 7.01(1H, dd),7.30(1H, d), 7.52(1H, [1,4′-bipiperidine]-1′- d), 7.90(2H, dd)sulfonamide 10B N-[[4-(3,4- 526/528 (DMSO) 1.16(2H, qd), 1.50-1.61(4H,m), 1.87-1.94(2H, dichlorophenoxy)[1,4′- m), 2.28-2.46(5H, m),2.69-2.75(2H, m), 4.18-4.27 bipiperidin]-1′- (2H, m), 4.39(1H, septet),6.97(1H, dd), 7.11(2H, t), 7.20 yl]carbonyl]-2- (1H, td), 7.25(1H, d),7.48(1H, d), 7.74(1H, d) methylbenzenesulfona- mide sodium salt 10CN-[[4-(3,4- 512/514 (DMSO) 1.16(2H, qd), 1.49-1.62(4H, m), 1.87-1.94(2H,dichlorophenoxy)[1,4′- m), 2.27-2.46(5H, m), 2.69-2.75(2H, m), 4.17-4.26bipiperidin]-1′- (2H, m), 4.39(1H, septet), 6.97(1H, dd), 7.25(1H, d),7.29- yl]carbonyl]- 7.33(3H, m), 7.48(1H, d), 7.69-7.72(2H, m)benzenesulfonamide sodium salt 10D N-[[4-(4-chloro-2- 506/508 (DMSO)1.10-1.21(2H, m), 1.54-1.65(4H, m), 1.83- methylphenoxy)[1,4′- 1.91(2H,m), 2.28(3H, s), 2.12(3H, d), 2.30-2.46(5H, m), bipiperidin]-1′-2.65-2.72(2H, m), 4.20(2H, d), 4.32-4.39(1H, m), 6.97 yl]carbonyl]-4-(1H, d), 7.10(2H, d), 7.13(1H, dd), 7.19(1H, dd), 7.58 (2H,methyl-benzenesulfonamide d) sodium salt 16B 4-(3,4- 604/606/608 274-276dichlorophenoxy)-N- recrystallised [[4-(1,1- from DMSO-dimethylethyl)phenyl] methanol. sulfonyl]-[1,4′- bipiperidine]-1′-sulfonamide

[0502] The preparations of certain intermediates are now presented.

Method A

[0503] [1,4′]Bipiperidinyl-4-ol

[0504] 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (20 g) and4-hydroxypiperidine (6.7 g) were stirred together in dichloroethane (200ml) with acetic acid (4 ml) at RT for 30 minutes. Sodiumtriacetoxyborohydride (23 g) was then added and the mixture stirred atRT overnight. The mixture was evaporated to dryness and the residuetaken into water, extracted with diethyl ether (3×200 ml), the aqueouswas basified to pH 9-10 and extracted with dichloromethane (3×200 ml).The dichloromethane extracts were combined, dried (MgSO₄) and evaporatedto leave an oil (19 g). The oil was dissolved in methanol (300 ml) andtreated with concentrated hydrochloric acid (5 ml). The mixture wasstirred overnight and then evaporated to dryness to leave the titlecompound as the hydrochloride salt (15 g).

[0505]¹H NMR (400 MHz, DMSO-D6) δ 1.6-2.4 (m, 9H), 2.8-3.5 (m, 8H), 3.62(m, 1H), 3.95 (s, 1H), 9.29 and 9.059 (bs, 2H), 10.9 and 11.09 (bs, 1H).

Method B

[0506] 4-(3,4-Dichlorophenoxy)piperidine

[0507] Step a: tert-Butyl4-(3,4-dichlorophenoxy)-1-piperidinecarboxylate

[0508] Diethyl azodicarboxylate (41.0 ml) was added to a solution oftriphenylphosphine (62.9 g) in tetrahydrofuran (800 ml) at 0° C. After15 minutes 3,4-dichlorophenol (39.1 g) was added, after a further 15minutes tert-butyl 4-hydroxy-1-piperidinecarboxylate (48.3 g) intetrahydrofuran (400 ml) was added dropwise over 30 min. The solutionwas stirred at room temperature for 16 hours and concentrated to a smallvolume. Purification by chromatography (ethyl acetate:iso-hexane 95:5)gave the sub-title compound as an oil (61.3 g).

[0509] MS: APCI(+ve): 246/248 (M-BOC+2H)

[0510] Step b: 4-(3,4-Dichlorophenoxy)piperidine

[0511] The product from Step a was dissolved in dichloromethane (600 ml)and trifluoroacetic acid (300 ml) was added. After 24 hours at roomtemperature the solution was evaporated and the resultant gum trituratedunder ether to give the sub-title product as a solid (36.6 g). The freebase was liberated by addition of aqueous NaOH (2M) and extraction withethyl acetate followed by evaporation of solvent to give the titlecompound as a gum (25 g).

[0512]¹H NMR: δ (CDCl₃) 1.77 (1H, br s), 2.05-2.26 (4H, m), 3.20-3.49(4H, m), 4.61 (1H, s), 6.69-7.52 (3H, m).

Method C

[0513] 4-(3,4-Dichlorophenoxy)-[1,4′]bipiperidine

[0514] Step a: 4-(3,4-Dichlorophenoxy)-[1,4′]bipiperidinyl-1′-carboxylicacid tert-butyl ester

[0515] 4-(3,4-Dichlorophenoxy)piperidine (1.5 g) was dissolved in1,2-dichloroethane (21 ml). 1-Boc-4-piperidone was added (1.21 g)followed by NaBH(OAc)₃ (1.81 g) and acetic acid (0.37 g). After 18 hoursat room temperature aqueous NaOH (1M) solution and diethyl ether wereadded. The product was extracted with diethyl ether, the combinedorganic extracts dried with MgSO₄ and concentrated. Purification bychromatography (dichloromethane methanol 92:8) gave the sub-titleproduct (1.97 g; MS: APCI(+ve): 429/431 (M+H)).

[0516] Step b: 4-(3,4-Dichloro-phenoxy)-[1,4′]bipiperidine

[0517] The product of Step a was dissolved in dichloromethane (30 ml)and trifluoroacetic acid (15 ml) was added. After 4 hours at roomtemperature the solution was evaporated and the resultant gum trituratedunder ether to give the trifluoroacetate salt of the sub-titled productas a solid (1.15 g). The free base was liberated by addition of aqueousNaOH (2M) and extraction with ethyl acetate followed by evaporation ofsolvent to give the sub-title compound as a solid (0.68 g).

[0518]¹H NMR: δ(CDCl₃) 1.38-1.51 (2H, m), 1.74-2.02 (6H, m), 2.38-2.50(3H, m), 2.56-2.61 (2H, m), 2.79-2.86 (2H, m), 3.14-3.18 (2H, m),4.22-4.28 (1H, m), 6.73-7.32 (3H, m).

[0519] The following intermediates were prepared in a similar manner toMethod C: MS: (M + H) 4-(4-chloro-2-methylphenoxy)-1,4′-bipiperidine309/311 4-(2-chloro-4-fluorophenoxy)-1,4′-bipiperidine 313/3154-(3,4-diflorophenoxy)-1,4′-bipiperidine 2974-(2,4-dichlorophenoxy)-1,4′-bipiperidine 329/3314-(2,4-dichloro-3-methylphenoxy)-1,4′-bipiperidine 343/3454-(3,4-dichloro-2-methylphenoxy)-1,4′-bipiperidine 343/345 ¹4-[(3,4-Dichlorophenyl)methyl]-1,4′-bipiperidine 327/329 ²2-([1,4′-bipiperidin]-4-yloxy)-5-chloro-pyridine ³

Method D

[0520] 4-(3-Chloro-4-fluoro-phenoxy)-piperidine

[0521] DEAD (0.43 ml) was added to a solution of triphenylphosphine(0.72 g), 3-chloro-4-fluorophenol (0.403 g) and4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.5 g) in THFat RT. The resulting mixture was stirred overnight, HCl in dioxan (2 mlof 4M) was added and the mixture stirred at RT overnight. The mixturewas then evaporated to dryness and triethylamine (5 ml) was added. Themixture was evaporated and the residue was dissolved in methanol (10ml), placed onto a SCX cartridge (Varian, 10 g, SCX cartridge availablefrom International Sorbent Technology Isolute® Flash SCX-2) and eluted:first with methanol then with 10% NH₃ in methanol. The basic fractionswere combined and evaporated to give the product as an oil (0.6 g).

[0522]¹H NMR (299.946 MHz, DMSO-D6) δ 1.34-1.46 (2H, m), 1.83-1.91 (2H,m), 2.53-2.59 (2H, m), 2.87-2.96 (2H, m), 3.22-3.39 (1H, m), 4.39 (1H,septet), 6.92-6.98 (1H, m), 7.17-7.20 (1H, m), 7.30 (1H, t).

[0523] The following intermediates were prepared in similar manner toMethod D: MS: (M + H) 4-(4-chloro-2-methyl-phenoxy)-piperidine 226/2284-(4-chloro-3-fluoro-phenoxy)-piperidine 230/2324-(4-chloro-2-methoxy-phenoxy)-piperidine 242/2444-(4-fluoro-2-methoxy-phenoxy)-piperidine 2264-(4-methoxy-phenoxy)-piperidine 208 4-p-tolyloxy-piperidine 1924-(4-chloro-3-methyl-phenoxy)-piperidine 226/2284-(4-chloro-phenoxy)-piperidine 212/214 4-(4-fluoro-phenoxy)-piperidine196 4-(2,4-dichloro-phenoxy)-piperidine 246/2484-(2-chloro-4-fluoro-phenoxy)-piperidine 230/2324-(2,4-difluoro-phenoxy)-piperidine 2144-(4-chloro-2-fluoro-phenoxy)-piperidine 230/2324-(4-fluoro-2-methyl-phenoxy)-piperidine 2104-(4-chloro-2,6-dimethyl-phenoxy)-piperidine 240/2424-(2,3-dichloro-phenoxy)-piperidine 246/2484-(2,5-dichloro-phenoxy)-piperidine 246/2484-(2-chloro-4-methyl-phenoxy)-piperidine 226/2284-(2-chloro-5-methyl-phenoxy)-piperidine 226/2281-[3-methyl-4-(piperidin-4-yloxy)-phenyl]-ethanone 2344-(2-chloro-6-methyl-phenoxy)-piperidine 226/2284-(4-chloro-2-ethyl-phenoxy)-piperidine 240/2427-(piperidin-4-yloxy)-quinoline 229 4-(2-tert-butyl-phenoxy)-piperidine234 4-(indan-5-yloxy)-piperidine 2184-(4-chloro-2-cyclohexyl-phenoxy)-piperidine 294/2965-chloro-2-(piperidin-4-yloxy)-benzamide 255/2574-(4-chloro-2-isoxazol-5-yl-phenoxy)-piperidine 279/2814-(5-chloro-2-methyl-phenoxy)-piperidine 226/228 4-phenoxy-piperidine178 4-(2,4-dichloro-6-methyl-phenoxy)-piperidine 260/2624-(3-chloro-4-methyl-phenoxy)-piperidine 226/2285-chloro-2-(piperidin-4-yloxy)-benzonitrile 237/2394-(2,4-dichloro-3-methyl-phenoxy)-piperidine 260/2624-(2-ethyl-4-fluoro-phenoxy)-piperidine 2244-(4-methanesulfonyl-phenoxy)-piperidine 2974-(3,4-dichloro-2-methylphenoxy)-piperidine 260/262

Method E

[0524] 4-(3,4-Dichlorophenoxy)-4′-methyl-1,4′-bipiperidinedihydrochloride

[0525] a) 1,1-Dimethylethyl4′-cyano-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′carboxylate

[0526] 4-(3,4-Dichlorophenoxypiperidine) (Method B step b; 500 mg) wasdissolved in dichloroethane (2 ml) with 1-Boc-4-piperidone (446 mg).Titanium teraisopropoxide (0.85 ml) was added and the mixture wasstirred overnight. The solvent was evaporated and toluene (5 ml) wasadded followed by diethylaluminium cyanide (3 ml of 1M solution intoluene). The mixture was stirred for 3 h, then ethyl acetate was added(5 ml) followed by water (0.5 ml) and the mixture was stirred for afurther 2 h. The mixture was filtered through a GF filter paper, andevaporated to give the subtitle compound (912 mg; MS [M+H]+ (APCI+)454/456).

[0527]¹H NMR (399.98 MHz, CD₃OD) δ 1.36 (s, 9H), 1.57-1.77 (m, 4H),1.90-1.99 (m, 2H), 2.04-2.12 (m, 2H), 2.44-2.52 (m, 2H), 2.77-2.87 (m,2H), 3.02-3.13 (m, 2H), 3.82 (dt, 2H), 4.31-4.40 (m, 1H), 6.81 (dd, 1H),7.02 (d, 1H), 7.29 (d, 1H).

[0528] b) 1,1-Dimethylethyl4-(3,4-dichlorophenoxy)-4′-methyl-[1,4′-bipiperidine]-1′-carboxylate

[0529] 1,1-Dimethylethyl4′-cyano-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxylate (100mg) was dissolved in THF (6 ml). Methyl magnesium bromide (3M in ether,220 μl) was added and the mixture was stirred at RT for 2 h. Furthermethyl magnesium bromide (220 μl) was added and the solution was stirredfor a further 60 h. Potassium carbonate solution (saturated aqueous) wasadded and the mixture was extracted with DCM. The organic phase wasdried, filtered and evaporated to give the subtitle compound (100 mg; MS[M+H]⁺ (APCI+) 443/445).

[0530]¹H NMR (299.945 MHz, CD₃OD) δ 1.01 (s, 3H), 1.47 (s, 9H),1.69-1.84 (m, 4H), 1.97-2.08 (m, 2H), 2.42-2.52 (m, 2H), 2.81-2.92 (m,2H), 3.36-3.42 (m, 2H), 3.45-3.57 (m, 2H), 3.62-3.89 (m, 2H), 4.32-4.41(m, 1H), 6.89 (dd, 1H), 7.10 (d, 1H), 7.38 (d, 1H).

[0531] c) 4-(3,4-dichlorophenoxy)-4′-methyl-1,4′-bipiperidinedihydrochloride

[0532] 1,1-Dimethylethyl4-(3,4-dichlorophenoxy)-4′-methyl-[1,4′-bipiperidine]-1′-carboxylate(100 mg) was dissolved in ethanol (5 ml). Hydrogen chloride (2 ml of 4Min dioxan) was added and the solution was stirred overnight. Furtherhydrogen chloride solution (2 ml) was added and the mixture was stirredfor a further 2 h. The solvents were evaporated to give the titlecompound (95 mg; MS [M+H]⁺ (APCI+) 343/345).

Method F

[0533] trans Sodium4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate

[0534] a) Ethyl4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate

[0535] 4-(3,4-Dichlorophenoxy)piperidine (Method B, 1.44 g), ethyl4-oxocyclohexanecarboxylate (1.0 g) and acetic acid (0.34 ml) werecombined in THF 10 ml and the solution was cooled in ice. Sodiumtriacetoxy borohydride (1.45 g) was added and the mixture was stirredovernight and allowed to come to ambient temperature. The reactionmixture was poured onto a stirred saturated aq solution of sodiumbicarbonate. The mixture was extracted with ethyl acetate thrice, theorganic phases were washed with brine, dried, filtered and evaporated.The residue was purified on an SCX cartridge (International SorbentTechnology Isolute® Flash SCX-2), washed with methanol and then producteluted with 0.7M ammonia in methanol. Further purification bychromatography (silica, 90:9:1 DCM:methanol:triethylamine) gave thesubtitle compound (1.59 g; MS [M+H]⁺ (APCI+) 400/402) as a mixture ofcis/trans isomers.

[0536]¹H NMR (399.98 MHz, CD₃OD) δ 1.23 (t), 1.25 (t), 1.28-1.59 (m),1.70-1.81 (m), 1.96-2.07 (m), 2.17-2.27 (m), 2.32-2.40 (m), 2.45-2.56(m), 2.581-2.61 (m), 2.80-2.89 (m), 3.30 (quintet), 4.10 (q), 4.14 (q),4.34-4.40 (m), 6.88 (dd), 6.88 (dd), 7.09 (d), 7.09 (d), 7.37 (d), 7.37(d).

[0537] b) trans Sodium4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate

[0538] Ethyl4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate (0.97g) was added to a solution of sodium ethoxide in ethanol (prepared fromsodium (1.28 g) and ethanol (100 ml)) the solution was heated to refluxovernight. Acetic acid was added and the solvent was evaporated. Ethylacetate, water and sodium hydroxide were added to the residue and aninsoluble white solid formed which was collected by filtration and driedin vacuo to give the sub-titled compound (469 mg; MS [M−Na]⁻ (APCI−)370/372) containing sodium acetate.

[0539]¹H NMR (399.98 MHz, CD₃OD) δ 1.27-1.38 (m, 2H), 1.46 (q, 2H),1.72-1.81 (m, 2H), 1.95-2.09 (m, 7H), 2.40 (t, 1H), 2.55 (td, 2H),2.84-2.91 (m, 2H), 4.39 (septet, 1H), 6.89 (dd, 1H), 7.10 (d, 1H), 7.37(d, 1H).

Method G

[0540] 4-(3,4-Dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide

[0541] 4-(3,4-Dichlorophenoxy)-1,4′-bipiperidine (5 g, 0.0152 mol) andsulfamide (1.45 g, 0.0152 mol) were stirred together in dioxan (150 ml)at reflux for 24 hours. The resulting mixture was cooled to ambienttemperature, evaporated to dryness and the residue was triturated withether to give the title compound as a tan solid (5 g; MS APCI 409/411(M+H)).

[0542]¹H NMR (399.98 MHz, DMSO) δ 1.38-2.03 (m, 6H), 2.25-2.45 (m, 6H),2.66-2.84 (m, 3H), 3.41-3.53 (m, 2H), 4.35-4.47 (m, 1H), 6.31-6.45 (m,2H), 6.91-7.03 (m, 1H), 7.18-7.31 (m, 1H), 7.43-7.55 (m, 1H).

Method H

[0543] 4-(3,4-Dichlorophenoxy)-[1,4′-bipiperidine]-1′-carboxamide.

[0544] 4-(3,4-Dichlorophenoxy)-1,4′-bipiperidine (2.0 g) was dissolvedin glacial acetic acid (0.608 ml), the solution was diluted with water(6 ml) and added with stirring to a solution of sodium cyanate (0.395 g)in warm water (3 ml). The reaction was allowed to stand for 30 mins. 2MSodium hydroxide solution was added until the solution was alkaline. Theresulting precipitate was collected and washed with water followed bydichloromethane and then dried to leave the sub-title compound (1.3 g;ES+ 372/374).

[0545]¹H NMR (399.98 MHz, DMSO) δ 1.20-1.31 (m, 2H), 1.51-1.61 (m, 2H),1.62-1.69 (m, 2H), 1.88-1.95 (m, 2H), 2.32-2.44 (m, 3H), 2.55-2.64 (m,2H), 2.70-2.77 (m, 2H), 3.92-3.99 (m, 2H), 4.37-4.44 (m, 1H), 5.86 (s,2H), 6.95-6.99 (m, 1H), 7.24-7.25 (m, 1H), 7.49 (d, 1H).

Method I

[0546] 2,4-Dichloro-3-fluorophenol

[0547] a) N,N-Diethyl-4-chloro-3-fluorophenyl carbamate

[0548] A solution of 4-chloro-3-fluorophenol (26.9 g) anddiethylcarbamoyl chloride (25 g) in pyridine (100 ml) was heated to 100°C. for 12 h and then allowed to cool. Water (100 ml) was added and theproduct was extracted with diethylether/pentane (1:1) (50 ml×2). Thecombined organic extracts were washed with HCl (2M, 70 ml), NaOH (2M, 75ml) and dried (MgSO₄), filtered and evaporated to give the subtitlecompound as an oil (37.7 g)

[0549]¹H NMR δ (CDCl₃) 1.18-1.26 (6H, m), 3.35-3.44 (4H, m), 6.90 (1H,ddd), 6.99-7.02 (1H, m), 7.35 (1H, t)

[0550] b) N,N-Diethyl-2,4-dichloro-3-fluorophenyl carbamate

[0551] To a solution of N,N-diethyl-4-chloro-3-fluorophenyl carbamate(15 g) in THF (100 ml) and TMEDA (9.7 ml) at −90° C. was added secBuLi(1.3M, 49.5 ml) whilst maintaining the temperature between −80° C. and−90° C. The mixture was stirred at −80° C. for 2 h.1,1,1,2,2,2-Hexachloroethane (17.39 g) as a solution in THF (50 ml) wasadded. During this period the reaction was allowed to warm to 0° C.Water (50 ml) was added and the product was extracted with pentane. Thecombined organic extracts were dried (MgSO₄) and filtered. Evaporationof solvent and purification by HPLC (Waters XTerra® column)(gradient(25% MeCN/NH3(aq) (0.1%) to 95% MeCN//NH3(aq) (0.1%)) gave the subtitlecompound as an oil (9.3 g).

[0552]¹H NMR δ (CDCl₃) 1.19-1.32 (6h, m), 3.36-3.51 (4H, m), 7.03 (1H,dq), 7.26-7.33 (1H, m)

[0553] 2,4-Dichloro-3-fluorophenol

[0554] N,N-Diethyl-2,4-dichloro-3-fluorophenyl carbamate (8.14 g) wasdissolved in THF (17 ml). A solution of lithium aluminium hydride (33 mlof 1M in THF) was added dropwise and the resulting solution was stirredovernight. Ethanol was added followed by hydrochloric acid (2M, 17 ml).The resulting suspension was filtered and the solid was washed withether. The phases were separated, the aqueous phase was extracted thricewith ether and the combined organic phases were dried (MgSO₄), filtered-and evaporated to give the title compound (3.4 g).

[0555]¹H NMR δ (CD₃OD) 6.65 (1H, dd), 7.11 (1H, t)

Method J

[0556] 2,6-Dimethyl-benzenesulfonamide

[0557] To a solution of 2,6-dimethyl-benzenethiol (2 ml) in water (20ml), chlorine gas was introduced over 15 minutes resulting inprecipitation of an orange solid. The reaction was left to stir in astoppered flask for a further 60 minutes. An excess of ammonia solution(0.88 sg) was added and the mixture was left to stir for 12 h. Thereaction was evaporated to remove ammonia and then filtered. The solidwas washed with water followed by iso-hexane to give the title compound.

[0558] MS [M−H]⁻ (ES−) 184

[0559]¹H NMR δ (DMSO) 2.59 (6H, s), 7.18 (2H, d), 7.27 (2H, s), 7.30(1H, t)

Method K

[0560] trans4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylic acid

[0561] a) trans Ethyl4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate

[0562] Ethyl4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate (methodF, step a, 0.97 g) was added to a solution of sodium ethoxide preparedfrom sodium (1.28 g) and ethanol (100 ml). The resultant solution washeated under reflux for 18 h. Acetic acid (0.1 ml) was added and thesolvent was evaporated. Ethyl acetate, water and sodium hydroxide wereadded to the residue and separated. The aqueous phase was extractedtwice with ethyl acetate-methanol mixtures and the combined organicphases were washed with brine, dried (MgSO₄), filtered and evaporated togive the subtitle compound as an oil.

[0563] MS [M+H]⁺ (APCI+) 400/402

[0564]¹H NMR of major isomer (ca 3.5:1 ratio) δ (acetone) 1.20 (3H, t),1.27-1.46 (4H, m), 1.57 1.71 (3H, m), 1.84-1.90 (2H, m), 1.95-2.02 (4H,m), 2.15-2.23 (1H, m), 2.27-2.41 (2H, m), 2.46 (2H, ddd), 4.06 (2H, q),4.40 (1H, septet), 6.95 (1H, dd), 7.15 (1H, d), 7.43 (1H, d)

[0565] b) trans4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylic acid

[0566] trans Ethyl4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanecarboxylate (0.8 g)was dissolved in t-BuOH (180 ml) at 38° C. To this was added Candiarugosa lipase powder (3 g). This was stirred for 30 minutes then water(20 ml) was added over 4 h. The mixture was then stirred for 48 h andfiltered. The enzyme was washed with 9:1 t-BuOH-water (2×20 ml) and thefiltrate was evaporated. Ethyl acetate was added to the residue and thendecanted. The resultant solid was dissolved in methanol/DMSO and waspurified by HPLC (Waters XTerra® column with at-column dilution ofsample) (gradient (5% MeCN/NH3(aq) (0.2%) to 40% MeCN//NH3(aq) (0.2%)]gave the title compound (0.44 g) as a white solid.

[0567] m.pt. 167-168° C.

[0568] MS [M+H]⁺ (ES+) 372/374

[0569]¹H NMR δ (DMSO) 1.19-1.36 (4H, m), 1.50-1.59 (2H, m), 1.78 (2H,d), 1.87-1.96 (4H, m), 2.09 (1H, td), 2.24-2.32 (1H, m), 2.38 (2H, td),2.72 (2H, dt), 4.39 (1H, septet), 6.97 (1H, dd), 7.24 (1H, d), 7.49 (1H,d)

Method L

[0570] 1,1-Dimethylethyl[4-(3,4-dichlorophenoxy)-1,4′-bipiperidin-1′-yl]sulfonylcarbamate

[0571] tert-Butanol (0.48 ml) in dichloromethane (2 ml) was added to asolution of chlorosulfonylisocyanate (0.43 ml) in dichloromethane (5 ml)stirring at 0° C. The resulting solution was then added to a solution of4-(3,4-dichlorophenoxy)-1,4′-bipiperidine (1.6 g) and triethylamine(0.77 ml) in dichloromethane (20 ml) at 0° C. After stirring at 0° C.for 2 h, the reaction mixture was washed with 0.1M hydrochloric acid (30ml), dried (MgSO₄) and evaporated. The residue was triturated withdiethylether (20 ml) to give the title compound as a white solid. (1.9g)

[0572]¹H NMR δ (DMSO) 1.44 (9H, s), 1.64-1.77 (2H, m), 1.94-2.08 (2H,m), 2.15-2.27 (4H, m), 2.86 (2H, t), 3.03-3.18 (2H, m), 3.28-3.53 (3H,m), 3.76 (2H, d), 4.59-4.81 (1H, m), 6.99-7.11 (1H, m), 7.33-7.39 (1H,m), 7.52-7.58 (1H, m)

EXAMPLE 17 Pharmacological Analysis: Calcium Flux [Ca²⁺]_(i) Assay

[0573] Human Eosinophils

[0574] Human eosinophils were isolated from EDTA anticoagulatedperipheral blood as previously described (Hansel et al., J. Immunol.Methods, 1991, 145, 105-110). The cells were resuspended (5×10⁶ ml⁻¹)and loaded with 5 μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (MolecularProbes) in low potassium solution (LKS; NaCl 118 mM, MgSO₄ 0.8 mM,glucose 5.5 mM, Na₂CO₃ 8.5 mM, KCl 5 mM, HEPES 20 mM, CaCl₂ 1.8 mM, BSA0.1%, pH 7.4) for one hour at room temperature. After loading, cellswere centrifuged at 200 g for 5 min and resuspended in LKS at 2.5×10⁶ml⁻¹. The cells were then transferred to 96 well FLIPr plates(Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5 μMfibronectin for two hours) at 25 μl/well. The plate was centrifuged at200 g for 5 min and the cells were washed twice with LKS (200 μl; roomtemperature).

[0575] A compound of the Examples was pre-dissolved in DMSO and added toa final concentration of 0.1%(v/v) DMSO. Assays were initiated by theaddition of an A₅₀ concentration of eotaxin and the transient increasein fluo-3 fluorescence (l_(Ex)=490 nm and l_(Em)=520 nm) monitored usinga FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices,Sunnyvale, U.S.A.).

[0576] Compounds of the Examples were found to be antagonists if theincrease in fluorescence induced by eotaxin (a selective CCR3 agonist)was inhibited in a concentration dependent manner. The concentration ofantagonist required to inhibit the fluorescence by 50% can be used todetermine the IC₅₀ for the antagonist at the CCR3 receptor.

Human Eosinophil Chemotaxis

[0577] Human eosinophils were isolated from EDTA anticoagulatedperipheral blood as previously described (Hansel et al., J. Immunol.Methods, 1991, 145, 105-110). The cells were resuspended at 10×10⁶ ml⁻¹in RPMI containing 200 IU/ml penicillin, 200 μg/ml streptomycin sulfateand supplemented with 10% HIFCS, at room temperature.

[0578] Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C.with 7 μl of either vehicle or compound (100× required finalconcentration in 10% DMSO). The chemotaxis plate (ChemoTx, 3 μm pore,Neuroprobe) was loaded by adding 28 μl of a concentration of eotaxin 0.1to 100 nM (a selective CCR3 agonist over this concentration range)containing a concentration of a compound according to the Examples orsolvent to the lower wells of the chemotaxis plate. The filter was thenplaced over the wells and 25 μl of eosinophil suspension were added tothe top of the filter. The plate was incubated for 1 hr at 37° C. in ahumidified incubator with a 95% air/5% CO₂ atmosphere to allowchemotaxis.

[0579] The medium, containing cells that had not migrated, was carefullyaspirated from above the filter and discarded. The filter was washedonce with phosphate buffered saline (PBS) containing 5 mM EDTA to removeany adherent cells. Cells that had migrated through the filter werepelleted by centrifugation (300×g for 5 mins at room temperature) andthe filter removed and the supernatant transferred to each well of a96-well plate (Costar). The pelleted cells were lysed by the addition of28 μl of PBS containing 0.5% Triton x100 followed by two cycles offreeze/thawing. The cell lysate was then added to the supernatant. Thenumber of eosinophils migrating was quantified according to the methodof Strath et al., J. Immunol. Methods, 1985, 83, 209 by measuringeosinophil peroxidase activity in the supernatant.

[0580] Compounds of the Examples were found to be antagonists of eotaxinmediated human eosinophil chemotaxis if the concentration response toeotaxin was shifted to the right of the control curve. Measuring theconcentration of eotaxin required to give 50% chemotaxis in the presenceor absence of compounds enables the apparent affinity of the compoundsat CCR3 to be calculated.

1. A compound of formula (I):

wherein: T is C(O) or S(O)₂; W is C(O) or S(O)₂; X is CH₂, O or NH; Y isCR⁵ or N; R¹ is optionally substituted aryl or optionally substitutedheterocyclyl; R² is hydrogen or C₁₋₆ alkyl; R³ is hydrogen or optionallysubstituted C₁₋₆ alkyl; R⁴ is alkyl, optionally substituted aryl,optionally substituted aralkyl or optionally substituted heterocyclyl;R⁵ is hydrogen or C₁₋₆ alkyl; wherein the foregoing aryl andheterocyclyl moieties are optionally substituted by: halogen, cyano,nitro, hydroxy, oxo, S(O)_(p)R²⁵, OC(O)NR⁶R⁷, NR⁸R⁹, NR¹⁰C(O)R¹¹,NR¹²C(O)NR¹³R¹⁴, S(O)₂NR¹⁵R¹⁶, NR¹⁷S(O)₂R¹⁸, C(O)NR¹⁹R²⁰, C(O)R²¹,CO₂R²², NR²³CO₂R²⁴, C₁₋₆ alkyl, CF₃, C₁₋₆ alkoxy(C₁₋₆)alkyl, C₁₋₆alkoxy, OCF₃, C₁₋₆ alkoxy(C₁₋₆)alkoxy, C₁₋₆ alkylthio, C₂₋₆ alkenyl,C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl (itself optionally substituted by C₁₋₄alkyl or oxo), methylenedioxy, difluoromethylenedioxy, phenyl,phenyl(C₁₋₄)alkyl, phenoxy, phenylthio, phenyl(C₁₋₄)alkoxy, heteroaryl,heteroaryl(C₁₋₄)alkyl, heteroaryloxy or heteroaryl(C₁₋₄)alkoxy; whereinany of the immediately foregoing phenyl and heteroaryl moieties areoptionally substituted with halogen, hydroxy, nitro, S(O)_(q)(C₁₋₄alkyl), S(O)₂NH₂, cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl),C(O)(C₁₋₄ alkyl), CF₃ or OCF₃; p and q are, independently, 0, 1 or 2;R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁹, R²⁰, R²¹,R²² and R²³ are, independently, hydrogen, C₁₋₆ alkyl (optionallysubstituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl), CH₂(C₂₋₆ alkenyl),phenyl (itself optionally substituted by halogen, hydroxy, nitro, NH₂,NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) orheterocyclyl (itself optionally substituted by halogen, hydroxy, nitro,NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂, S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂,S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂, cyano, C₁₋₄ alkyl, C₁₋₄alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂, CO₂H, CO₂(C₁₋₄alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃or OCF₃); alternatively NR⁶R⁷, NR⁸R⁹, NR¹³R¹⁴, NR¹⁵R¹⁶, NR¹⁹R²⁰ orN(C₁₋₄ alkyl)₂ may, independently, form a 4-7 membered heterocyclicring, azetidine, pyrrolidine, piperidine, azepine, 1,4-morpholine or1,4-piperazine, the latter optionally substituted by C₁₋₄alkyl on thedistal nitrogen; R²⁵, R¹⁸ and R²⁴ are, independently, C₁₋₆ alkyl(optionally substituted by halogen, hydroxy or C₃₋₁₀ cycloalkyl),CH₂(C₂₋₆ alkenyl), phenyl (itself optionally substituted by halogen,hydroxy, nitro, NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkylgroups may join to form a ring as described for R⁶ and R⁷ above),S(O)₂(C₁₋₄ alkyl), S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂(and these alkyl groups may join to form a ring as described for R⁶ andR⁷ above), cyano, C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl),C(O)N(C₁₋₄ alkyl)₂ (and these alkyl groups may join to form a ring asdescribed for R⁶ and R⁷ above), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄alkyl), NHS(O)₂(C₁₋₄ alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃) orheterocyclyl (itself optionally substituted by halogen, hydroxy, nitro,NH₂, NH(C₁₋₄ alkyl), N(C₁₋₄ alkyl)₂ (and these alkyl groups may join toform a ring as described for R⁶ and R⁷ above), S(O)₂(C₁₋₄ alkyl),S(O)₂NH₂, S(O)₂NH(C₁₋₄ alkyl), S(O)₂N(C₁₋₄ alkyl)₂ (and these alkylgroups may join to form a ring as described for R⁶ and R⁷ above), cyano,C₁₋₄ alkyl, C₁₋₄ alkoxy, C(O)NH₂, C(O)NH(C₁₋₄ alkyl), C(O)N(C₁₋₄ alkyl)₂(and these alkyl groups may join to form a ring as described for R⁶ andR⁷ above), CO₂H, CO₂(C₁₋₄ alkyl), NHC(O)(C₁₋₄ alkyl), NHS(O)₂(C₁₋₄alkyl), C(O)(C₁₋₄ alkyl), CF₃ or OCF₃); or an N-oxide thereof; or apharmaceutically acceptable salt thereof; or a solvate thereof.
 2. Acompound as claimed in claim 1 wherein X is O.
 3. A compound as claimedin claim 1 wherein R¹ is phenyl substituted with one or more offluorine, chlorine, C₁₋₄ alkyl or C₁₋₄ alkoxy.
 4. A compound as claimedin claim 1 wherein one of T and W is C(O) and the other is S(O)₂.
 5. Acompound as claimed in claim 1 wherein T is C(O).
 6. A compound asclaimed in claim 1 wherein W is S(O)₂.
 7. A compound as claimed in claim1 wherein Y is N.
 8. A compound as claimed in claim 1 wherein R² ishydrogen or methyl.
 9. A compound as claimed in claim 1 wherein R³ ishydrogen.
 10. A compound as claimed in claim 1 wherein R⁴ is substitutedphenyl, the substituents being chosen from those provided in claim 1.11. A process for preparing a compound formula (I) as claimed in claim 1comprising: a. when R³ is hydrogen, T is C(O) and Y is N, reacting acompound of formula (II):

 with an isocyanate of formula R⁴WN═C═O in the presence of a suitablesolvent at a suitable temperature; b. when T is C(O), W is S(O)₂ and Yis N, reacting a compound of formula (II) with a compound of formula(XXII):

c. when R³ is hydrogen, T is S(O)₂, W is C(O) and Y is N, reacting acompound of formula (IX):

 with a compound of formula (II) in the presence of a suitable base, ina suitable solvent and at a suitable temperature; d. when R³ ishydrogen, T is S(O)₂, W is C(O) and Y is N, reacting a compound offormula (XVIII):

 with an acyl halide R⁴COHal in the presence of a base, in a suitablesolvent, at room temperature; e. when R³ is hydrogen, T is S(O)₂, W isC(O) and Y is N, reacting a compound of formula (XIX):

 with an acyl halide R⁴COHal in the presence of a base, in a suitablesolvent, for example at room temperature; followed by deprotection ofthe carbamate so formed; f. when T and W are both S(O)₂ and Y is N,reacting a compound of formula (X):

 with a sulfonamide R⁴S(O)₂NHR³ in the presence of a base, in a suitablesolvent; g. when T and W are both S(O)₂ and Y is N, reacting a compoundof formula (XVIII) with a sulfonyl chloride R⁴SO₂Cl in the presence of abase, in a suitable solvent; h. when T is C(O), W is S(O)₂ and Y is CR⁵,can be prepared by firstly hydrolysing a compound of formula (XI):

 wherein the ester is preferably a C₁₋₆ alkyl group, and reacting theproduct so formed with R⁴S(O)₂NHR³ in the presence of an appropriatecoupling agent, in a suitable solvent; i. when T and W are both C(O) andY is CR⁵ or N, can be prepared by heating a compound of formula (XIV):

 in the presence of R⁴C(OR′)₂N(CH₃)₂ or R⁴C(OR′)₃, wherein R′ is methylor ethyl, or (OR′)₃ is (OCH₂)₃CCH₃; j. when T is S(O)₂, W is C(O) and Yis CR⁵, coupling a compound of formula (XV):

 to an acid R⁴CO₂H in the presence of an appropriate coupling agent, ina suitable solvent; k. when T and W are both S(O)₂ and Y is CH, couplinga compound of formula (XV):

 to a sulfonyl chloride R⁴S(O)₂Cl in the presence of a base and asolvent; l. wherein R³ is not hydrogen, can be prepared by alkylating acompound of formula (I) wherein R³ is hydrogen, with a suitablealkylating agent in the presence of a suitable base in a suitablesolvent; or, m. Y is CR⁵ and R⁵ is not hydrogen, may be prepared from acompound of formula (I) where Y is CH by reaction of the dianion (R³ isH) or monoanion (R³ is alkyl) (formed with a suitable base) with analkylating agent in a suitable solvent.
 12. A pharmaceutical compositioncomprising a compound of the formula (I), or a pharmaceuticallyacceptable salt thereof or a solvate thereof, and a pharmaceuticallyacceptable adjuvant, diluent or carrier. 13-14. (Canceled)
 15. A methodof treating a chemokine mediated disease state in a mammal sufferingfrom, or at risk of, said disease, which comprises administering to amammal in need of such treatment a therapeutically effective amount of acompound of formula (I), or a pharmaceutically acceptable salt, solvateor solvate of a salt thereof, as claimed in claim
 1. 16. A compound asclaimed in claim 1 which is:N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;4-Chloro-N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;2-Chloro-N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;N-[[4-(2-Chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;4-Chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;2-Chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluorobenzenesulfonamide;N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;N-[[4-(4-Chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;2-Chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;4-Chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluorobenzenesulfonamide;N-[[4-(2,4-Dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;2-Chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;4-Chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluorobenzenesulfonamide;N-[[4-(3,4-Dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluorobenzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methylbenzenesulfonamide;4-Chloro-N-[[4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;2-Chloro-N-[[4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]-3-trifluoromethylbenzenesulfonamide;3-Cyano-N-[[4-(3,4-dichlorophenoxy)-4′-methyl[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenemethanesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-methanesulfonamide;N-[[4-(4-Chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl benzenesulfonamide;N-[[4-(4-Chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;4-Chloro-N-[[4-(4-chloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-N,4-dimethylbenzenesulfonamide;N-[[4-[(3,4-Dichlorophenyl)methyl][1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;4-Chloro-N-[[4-[(3,4-dichlorophenyl)methyl][1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;N-[[4-[(3,4-Dichlorophenyl)amino]-[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methylbenzenesulfonamide;4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;3-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;3,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]benzenesulfonamide;3-Cyano-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethoxybenzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3,4-dimethoxy-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(3,3-dimethyl-2-oxo-1azetidinyl)-benzenesulfonamide; N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-hydroxy-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-(trifluoromethyl)benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-[[[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-benzoicacid, methyl ester; 2-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[5-[[[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-1,3,4thiadiazol-2-yl]-acetamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-(dimethylamino)-1naphthalenesulfonamide; N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-naphthalenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-dimethyl-5 thiazolesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(1-piperidinyl)-3pyridinesulfonamide; 5-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2 thiophenesulfonamide;5-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2thiophenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]tetrahydro-3thiophenesulfonamide; 1,1-dioxide4,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2thiophenesulfonamide;4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethylbenzenesulfonamide;4-n-Butyl-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;2,5-Dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3thiophenesulfonamide; 4-n-Butoxy-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(trifluoromethoxy)benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-1-methyl-1H-imidazole-4sulfonamide;5-Amino-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-1,3,4-thiadiazole-2sulfonamide;4-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2thiophenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(4-morpholinyl)-3pyridinesulfonamide; 6-Bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-pyridinesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(1,1-dimethylethyl)benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-methyl-2-pyridinesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluorobenzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(trifluoromethoxy)benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4,5-trifluorobenzenesulfonamide;5-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-difluorobenzenesulfonamide;4-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluorobenzenesulfonamide;3-Chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-fluoro-2-methylbenzenesulfonamide;N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-fluoro-benzenesulfonamide;2-chloro-N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;2-chloro-N-[[4-(3,4-dichloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(2,4-dichloro-3-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;2-chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-chloro-N-[[4-(4-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;2-chloro-N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;2-chloro-N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2-chloro-4-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;2-chloro-N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-chloro-N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2,4-dichloro-3-fluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;2-chloro-N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-chloro-N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(4-chlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;2-chloro-N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;4-chloro-N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(2,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;2-chloro-N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methyl-benzenesulfonamide;N-[[4-(3,4-difluorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methyl-benzenesulfonamide;N-[[4-(3-chloro-2-methylphenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;3-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-methoxy-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4,5-trifluoro-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluoro-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(dimethylamino)-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-methoxy-benzenesulfonamide;4-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;3,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;Methyl2-[[[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]amino]sulfonyl]-benzoate;2-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-benzenesulfonamide;5-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;4,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;4-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-dimethyl-benzenesulfonamide;2,5-dichloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-3-thiophenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-(trifluoromethoxy)-benzenesulfonamide;4-bromo-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-thiophenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-4-(trifluoromethoxy)-benzenesulfonamide;5-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,4-difluoro-benzenesulfonamide;4-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,5-difluoro-benzenesulfonamide;3-chloro-N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-5-fluoro-2-methyl-benzenesulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2,6-dimethyl-benzenesulfonamide;N-[[4-(3,4-Dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-propanesulfonamide;4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(2-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(2-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-(3-cyanobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(2,4-dichloro-3-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(2-chlorobenzoyl)-4-(2,4-dichloro-3-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(2,4-dichloro-3-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-[4-(dimethylamino)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-(4-ethylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-(2-chlorobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;N-(3-cyanobenzoyl)-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;N-benzoyl-4-(3,4-dichloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;N-benzoyl-4-(2,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;N-(3-cyanobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-fluorobenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(4-chloro-2-methylphenoxy)-N-[3-(methylsulfonyl)benzoyl]-[1,4′-bipiperidine]-1′-sulfonamide;N-(2-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;N-(4-chlorobenzoyl)-4-(4-chloro-2-methylphenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(2-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-methoxybenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-[(1,2-dihydro-1-oxo-4-isoquinolinyl)carbonyl]-[1,4′-bipiperidine]-1′-sulfonamide;N-(cyclohexylcarbonyl)-4-(3,4-dichlorophenoxy)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(2-methyl-1-oxopropyl)-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-(2-phenylacetyl)-[1,4′-bipiperidine]-1′-sulfonamide;N-[[4-(3,4-dichlorophenoxy)[1,4′-bipiperidin]-1′-yl]carbonyl]-2-propanesulfonamide;TransN-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-methyl-benzenesulfonamide;TransN-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-N,4-dimethyl-benzenesulfonamide;Trans4-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-methyl-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-methyl-benzenesulfonamide;Trans3-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;Trans4-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;Trans3,5-dichloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;Trans3-cyano-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-dimethoxy-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3,4-dimethoxy-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(3,3-dimethyl-2-oxo-1-azetidinyl)-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-(4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-hydroxy-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-(trifluoromethyl)-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;Trans2-[[[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]amino]-sulfonyl]-benzoicacid, methyl ester; Trans2-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;TransN-[5-[[[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]amino]sulfonyl]-1,3,4-thiadiazol-2-yl]-acetamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-5-(dimethylamino)-1-naphthalenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-naphthalenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,4-dimethyl-5-thiazolesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-(1-piperidinyl)-3-pyridinesulfonamide;Trans5-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-thiophenesulfonamide;Trans5-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-thiophenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]tetrahydro-3-thiophenesulfonamide,1,1-dioxide; Trans4,5-dichloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-thiophenesulfonamide;Trans4-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-dimethyl-benzenesulfonamide;Trans4-n-butyl-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;Trans2,5-dichloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-thiophenesulfonamide;Trans4-n-butoxy-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-(trifluoromethoxy)-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-1-methyl-1H-imidazole-4-sulfonamide;Trans5-amino-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-1,3,4-thiadiazole-2-sulfonamide;Trans4-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-thiophenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-(4-morpholinyl)-3-pyridinesulfonamide;Trans6-bromo-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-3-pyridinesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(1,1-dimethylethyl)-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-5-methyl-2-pyridinesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-difluoro-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(trifluoromethoxy)-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,4,5-trifluoro-benzenesulfonamide;Trans5-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,4-difluoro-benzenesulfonamide;Trans4-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,5-difluoro-benzenesulfonamide;Trans3-chloro-N-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-5-fluoro-2-methyl-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-methyl-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2-methoxy-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-2,6-dimethyl-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-methyl-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzenesulfonamide;TransN-[[4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-4-(dimethylamino)-benzenesulfonamide;4-(3,4-Dichlorophenoxy)-N-(2-methylbenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;4-(3,4-Dichlorophenoxy)-N-(4-methylbenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;4-(3,4-Dichlorophenoxy)-N-(4-chlorobenzoyl)-[1,4′-bipiperidine]-1′-carboxamide;4-(3,4-Dichlorophenoxy)-N-benzoyl-[1,4′-bipiperidine]-1′-carboxamide;4-(3,4-Dichlorophenoxy)-N-[(4-methylphenyl)sulfonyl]-[1,4′-bipiperidine]-1′-sulfonamide;4-(3,4-dichlorophenoxy)-N-[[4-(1,1-dimethylethyl)phenyl]sulfonyl]-[1,4′-bipiperidine]-1′-sulfonamide;[4-(3,4-dichlorophenoxy)-N-(phenylsulfonyl)-1,4′-bipiperidine]-1′-sulfonamide;TransN-benzoyl-4-[4-(3,4-dichlorophenoxy)-1-piperidinyl]-cyclohexanesulfonamide;TransN-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]carbonyl]-benzamide;or, TransN-[[4-[4-(3,4-Dichlorophenoxy)-1-piperidinyl]cyclohexyl]sulfonyl]-benzenesulfonamide.